Monti JM 2013

Jaime
M. Monti · S.R. Pandi-Perumal
S. Chokroverty Editors
Dopamine
and Sleep
Molecular, Functional, and Clinical
Aspects
Dopamine and Sleep
Jaime M. Monti S.R. Pandi-Perumal
•
S. Chokroverty
Editors
Dopamine and Sleep

Molecular, Functional, and Clinical Aspects
123
Editors
Jaime M. Monti S. Chokroverty
Department of Pharmacology Department of Neurology
and Therapeutics New Jersey Neuroscience Institute
School of Medicine Edison, NJ
Montevideo USA
Uruguay
S.R. Pandi-Perumal
Somnogen Canada Inc.
Toronto, ON
Canada
ISBN 978-3-319-46435-0 ISBN 978-3-319-46437-4 (eBook)

DOI 10.1007/978-3-319-46437-4
Library of Congress Control Number: 2016950910
© Springer International Publishing Switzerland 2016

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Preface
This first edition of Dopamine and Sleep: Molecular, Functional, and Clinical
Aspects provides comprehensive, yet up-to-date information pertaining to the role
of dopamine in sleep and wakefulness. The dopamine system is being increasingly
studied in the sleep field due to its prominent role in normal and aberrant brain
processes. Since dopamine plays a crucial role in brain processes such as alertness,
attention, cognitive organization, and mood regulation, it is particularly relevant to
understand how its actions affect sleep and wakefulness.
The study of dopamine has expanded markedly in recent years with the appli-
cation of electrophysiological, neurochemical, genetic, and neuropharmacological
techniques. These techniques are now being used successfully to help decipher the
role of dopamine in the regulation of sleep and wakefulness in health and disease.
The results are of great importance for the understanding and treatment of sleep
disruption in neurological and psychiatric disorders.
The editors believe that there is a current need to increase the awareness of the
latest developments in this multidisciplinary field. Hence, they have brought
together in the chapters of this volume a number of key studies with the overall aim
of summarizing and selectively presenting these developments. The contributors are
leading scientists in their respective fields.
The chapters in the first part of the book deal with preclinical studies on the role
of dopamine in the promotion of wakefulness and the inhibition of REM sleep. The
chapters in the second part relate to the effect of melanin-concentrating hormone
and orexin/hypocretin on dopaminergic neurons involved in the regulation of the
behavioral state. The third part of the volume focuses on the role of dopamine in
sleep disturbances in different disease conditions. These include Parkinson’s dis-
ease, narcolepsy, schizophrenia, depression, and restless legs syndrome. An attempt
is made also to see how a number of drugs that are used in these conditions produce
their effect by modifying dopamine function.
We have made every effort to ensure that the dosage recommendations are
accurate and in agreement with the standards and collective opinion accepted at the
time of publication. The formulations and usage described do not necessarily have
specific approval by the regulatory authorities of all countries. Since dosage
vii
viii Preface
regimens may be modified as new clinical research accumulates, readers are

strongly advised to check the prescribing information to see whether changes have
been made to the recommended dosages and/or contraindications for use.
Despite the editors’ best efforts, it is possible that certain errors may have
occurred in this volume. The authors and editors would be grateful for any criti-
cisms or comments to ensure that this volume continues to evolve in the future.
The volume is meant for specialized readers in the field of sleep medicine,
neurology, psychiatry, and life sciences, as well as for basic researchers in their
respective fields.
We hope that this multidisciplinary volume on dopamine will become yet
another contribution to advancing translational neuroscience, CNS drug develop-
ment, and the fields of clinical neurology and psychiatry.
Montevideo, Uruguay Jaime M. Monti

Toronto, USA S.R. Pandi-Perumal
Edison, USA S. Chokroverty
Acknowledgments
A few acknowledgments are in order. A project like this represents not the work of
one, but that of a community of scholars, and this is especially true of this volume.
The authoritative chapters of the book are written by some of the leading experts in
the field. We wish to thank these authors for their excellent contributions to this
volume. It was a great pleasure to compile this volume. We sincerely hope that it
will serve as an up-to-date and important source of information that covers the
recent trends in CNS drug discovery. As editors of this volume, we would like to
thank each other, because no coeditors could ever have been more patient,
understanding, and helpful. We treasure the friendship and respect that editing this
volume together has built.
We are grateful to our editor Beatrice Menz at Springer for her enthusiastic
support in bringing this undertaking to fruition. We also would like to thank the
staff at Springer for their enthusiastic support and guidance during the preparation
of the book. In particular, we would to thank Martina Himberger, Springer
Heidelberg, Germany, who inspired us to take up this project and set the publication
process in motion, and Abirami Purushothaman, SPS, Chennai, for coordinating the
publication process. They were wonderful to work with!
Finally, we would like to warmly thank our family for their support, encour-
agement, understanding, and especially patience. We also thank them for reminding
us that there are things in life beyond writing and editing volumes.
ix
Contents
Dopamine in REM Sleep Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Mudasir Ahmad Khanday, Raghunandan Kumar Yadav
and Birendra Nath Mallick
Dopaminergic Transmission and Wake-Promoting Effects
of Central Nervous System Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Ritchie E. Brown
The Effects of Dopamine Receptor Agonists
on the Sleep-Wake Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Andrea Herrera-Solís, Oscar Arias-Carrión, Andrea Sarro-Ramírez,
Mireille Salas-Crisóstomo and Eric Murillo-Rodríguez
Functional Interactions Between MCHergic and Dopaminergic
Neurons: Role in the Control of Wakefulness and Sleep . . . . . . . . . . . . . 47
Pablo Torterolo, Luciana Benedetto and Jaime M. Monti
Modulations of Ventral Tegmental Area (VTA) Dopaminergic
Neurons by Hypocretins/Orexins: Implications in Vigilance
and Behavioral Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Seiji Nishino and Noriaki Sakai
Alteration of Biological Rhythms in Diseases of the Central
Dopaminergic System: Focus on Parkinson’s Disease . . . . . . . . . . . . . . . 91
Santiago Perez-Lloret, Darío Acuña-Castroviejo, Victor Demaria-Pesce
and Daniel Cardinali
Parkinson’s Disease and Sleep/Wake Disturbances . . . . . . . . . . . . . . . . . 115
Todd J. Swick and William G. Ondo
Regulation and Modulation of Depression-Related Behaviours:
Role of Dopaminergic Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Basma Radwan, He Liu and Dipesh Chaudhury
xi
xii Contents
Depression, Sleep Disorders, and DA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Traci J. Speed and Patrick H. Finan
Sleep in Schizophrenia Patients and the Effects of Second
Generation Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Jaime M. Monti, Pablo Torterolo and Seithikurippu R. Pandi Perumal
Sleep in Narcolepsy and the Effects of Modafinil . . . . . . . . . . . . . . . . . . . 235
Michel Billiard
Long-Term Management Problems in Restless Legs Syndrome
(RLS)/Willis-Ekbom Disease (WED) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Sudhansu Chokroverty
Contributors
Darío Acuña-Castroviejo Institute of Biotechnology, Biomedical Research

Center, Health Science Technology Park, University of Granada, Granada, Spain
Oscar Arias-Carrión Unidad de Trastornos del Movimiento y Sueño (TMS),
Hospital General Dr. Manuel Gea González, México D.F., Mexico
Luciana Benedetto Laboratorio de Neurobiología Del Sueño, Departamento de
Fisiología, Facultad de Medicina, Universidad de la República, Montevideo,
Uruguay
Michel Billiard Department of Neurology, Gui de Chauliac Hospital, Montpellier,
France
Ritchie E. Brown In Vitro Neurophysiology Section, Laboratory of Neuroscience,
Department of Psychiatry, VA Boston Healthcare System and Harvard Medical
School, VA Medical Center Brockton, Brockton, MA, USA
Daniel Cardinali Department of Teaching and Research, Faculty of Medical
Sciences, Pontificia Universidad Católica Argentina BIOMED-UCA-CONICET,
Buenos Aires, Argentina
Dipesh Chaudhury Division of Science, New York University Abu Dhabi
(NYUAD), Abu Dhabi, United Arab Emirates
Sudhansu Chokroverty NJ Neuroscience Institute at JFK, Edison, NJ, USA;
Robert Wood Johnson Medical School, New Brunswick, NJ, USA
Victor Demaria-Pesce Directeur de Recherche, Institut National de La Santé et de
La Recherche Médicale (INSERM), Paris, France
Patrick H. Finan Department of Psychiatry and Behavioral Sciences, Johns
Hopkins University School of Medicine, Baltimore, USA
Andrea Herrera-Solís Unidad de Trastornos del Movimiento y Sueño (TMS),
Hospital General Dr. Manuel Gea González, México D.F., Mexico
xiii
xiv Contributors
Mudasir Ahmad Khanday School of Life Sciences, Jawaharlal Nehru University,

New Delhi, India
He Liu Division of Science, New York University Abu Dhabi (NYUAD), Abu
Dhabi, United Arab Emirates
Birendra Nath Mallick School of Life Sciences, Jawaharlal Nehru University,
New Delhi, India
Jaime M. Monti Departamento de Farmacología y Terapéutica, Facultad de
Medicina, Hospital de Clínicas, Universidad de la República, Montevideo,
Uruguay; Department of Pharmacology and Therapeutics, School of Medicine
Clinics Hospital, Montevideo, Uruguay
Eric Murillo-Rodríguez Laboratorio de Neurociencias Moleculares e Integrativas
Escuela de Medicina, División Ciencias de la Salud, Universidad Anáhuac Mayab,
Mérida, Yucatán, Mexico; Grupo de Investigación en Envejecimiento, División
Ciencias de la Salud, Universidad Anáhuac Mayab, Mérida, Yucatán, Mexico;
Grupo de Investigación Desarrollos Tecnológicos para la Salud, División de
Ingeniería y Ciencias Exactas, Universidad Anáhuac Mayab, Mérida, Yucatán,
Mexico
Seiji Nishino Sleep and Circadian Neurobiology Laboratory, Stanford University
School of Medicine, Palo Alto, CA, USA
William G. Ondo Methodist Neurological Institute, Houston, USA
Seithikurippu R. Pandi Perumal Somnogen Canada Inc., Toronto, ON, Canada
Santiago Perez-Lloret Cardiology Research Institute, University of Buenos Aires,
National Research Council (ININCA-UBA-CONICET), Buenos Aires, Argentina
Basma Radwan Division of Science, New York University Abu Dhabi
(NYUAD), Abu Dhabi, United Arab Emirates
Noriaki Sakai Sleep and Circadian Neurobiology Laboratory, Stanford University
School of Medicine, Palo Alto, CA, USA
Mireille Salas-Crisóstomo Laboratorio de Neurociencias Moleculares e
Integrativas Escuela de Medicina, División Ciencias de la Salud, Universidad
Anáhuac Mayab, Mérida, Yucatán, Mexico; Grupo de Investigación en
Envejecimiento, División Ciencias de la Salud, Universidad Anáhuac Mayab,
Mérida, Yucatán, Mexico
Andrea Sarro-Ramírez Laboratorio de Neurociencias Moleculares e Integrativas
Escuela de Medicina, División Ciencias de la Salud, Universidad Anáhuac Mayab,
Mérida, Yucatán, Mexico; Grupo de Investigación en Envejecimiento, División
Ciencias de la Salud, Universidad Anáhuac Mayab, Mérida, Yucatán, Mexico
Traci J. Speed Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine, Baltimore, USA
Contributors xv
Todd J. Swick University of Texas School of Medicine-Houston, Houston, TX,

USA; Apnix Sleep Disorders Centers, Houston, TX, USA; The Sleep Center at
North Cypress Medical Center, Cypress, TX, USA
Pablo Torterolo Laboratorio de Neurobiología Del Sueño, Departamento de
Fisiología, Facultad de Medicina, Universidad de la República, Montevideo,
Uruguay; Department of Physiology, School of Medicine, Montevideo, Uruguay
Raghunandan Kumar Yadav School of Life Sciences, Jawaharlal Nehru
University, New Delhi, India
Dopamine in REM Sleep Regulation
Mudasir Ahmad Khanday, Raghunandan Kumar Yadav

and Birendra Nath Mallick
Abstract The dopamine (DA)-ergic neurons are primarily localized in the sub-
stantia nigra (SN) and ventral tegmental area (VTA) of the brainstem. These neu-
rons are involved in diverse functions including control of movements, reward,
sleep-wakefulness and rapid eye movement sleep (REMS). Loss of these DA-ergic
neurons is associated with different behavioral disorders, including Parkinson’s
disease, depression, REMS behavior disorder (RBD) and notably in all these dis-
orders sleep including REMS is affected. These neurons receive projections from
the locus coeruleus (REM-OFF) and laterodorsal/pedunculopontinetegmentum
(REM-ON), neurons, and these modulate REMS. However, how these DA-ergic
neurons regulate REMS largely remains unknown. Relevant literatures suggest that
the DA-ergic neurons may have an indirect modulatory role, which however needs
confirmation.
Keyword Dopamine
Dopamine receptors
Parkinson’s disease REMS

behavior disorder Substantia nigra Ventral tegmental area
Abbreviations
DA Dopamine
DAT DA uptake transporter
EEG Electroencephalogram
EMG Electromyogram
EOG Electrooculogram
LC Locus coeruleus
LDT Latero-dorsal tegementum
NA Noradrenaline
NREMS Non-REMS
PD Parkinson’s disease
PPT Pedunclo-pontinetegmentum
M.A. Khanday R.K. Yadav B.N. Mallick (&)

School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India
e-mail: remsbnm@yahoo.com
© Springer International Publishing Switzerland 2016 1

J.M. Monti et al. (eds.), Dopamine and Sleep,
DOI 10.1007/978-3-319-46437-4_1
2 M.A. Khanday et al.
RBD REMS behavior disorder

REMS Rapid eye movement sleep
REMSD REMS deprivation
SN Substantia nigra
SNc SN pars compacta
SNr SN pars reticulata
VTA Ventral tegmental area
1 Sleep and REMS
Sleep is an instinct, naturally occurring, recurrent and reversible physiological

process. It is behaviorally characterized by reduced consciousness and reduced
responsiveness to external stimuli. This behavioral state has been objectively
identified and defined based on electrophysiological signals recorded from the
brain, (the electroencephalogram [EEG]), the muscles, (the electromyogram
[EMG]) and the eye movements, (the electrooculogram [EOG]). Based on these
signals the sleep has been divided into rapid eye movement sleep (REMS) and
non-REMS (NREMS) (Aserinsky and Kleitman 1953; Dement and Kleitman 1957;
Jouvet 1999). The REMS is unique as normally the subjects experience most of the
dreams in this state. Although the subjects spend the least amount of time in this
state, it holds a vital position throughout one’s life. For example, there is hardly any
psycho-somato-pathological condition (disease) when REMS is not affected
(Kupfer 1976; Gottesmann and Gottesman 2007; Palagini et al. 2013; Gilson et al.
2015) and experimental loss of REMS has been shown to affect brain development,
its excitability, concentration, memory, anxiety, mood disorder, hallucination and
host of other behavioral changes (Arnulf et al. 2000; Ranjan et al. 2010; Mallick
and Singh 2011) and its sustained loss has been shown to have fatal consequences
(Kushida et al. 1989). Indeed it has been proposed that “REMS serves house-
keeping function of the brain” (Mallick and Singh 2011). Thus, REMS appears to
exert its influence globally in the body and vice versa and therefore, it must be
regulated by varieties of neural as well as non-neural inputs, which would have
direct as well as modulatory effects on REMS in short- and long-term.
2 Neural Regulation of REMS
Based on experimental lesion, transection, single neuronal activity recording and

neuropharmacological studies it has been concluded that the pontine region in the
brainstem is necessary and critical for the generation and regulation of REMS
(Siegel 1989). On the basis of firing rate during REMS, neurons relatively more
active during REMS have been termed REM-ON, while those silent (or showing
significantly reduced firing) during REMS have been termed REM-OFF neurons.
Dopamine in REM Sleep Regulation 3
Based on such criteria a group of noradrenaline (NA)-ergic neurons in locus

coeruleus (LC) has been referred to as REM-OFF neurons, while a group of pre-
sumably cholinergic neurons in the laterodorsal/ pedunculopontine tegmentum
(LDT/PPT) region has been referred to as REM-ON neurons (McCarley and
Hobson 1975). Interaction among REM-ON and REM-OFF neurons is critical for
REMS regulation and based on independent studies the flip-flop model for REMS
regulation was proposed (Hobson et al. 1975; Sakai et al. 1981; Lu et al. 2006b).
Although the basic tenet of the flip-flop model appears to be correct, research has
shown that the REM-ON and REM-OFF neurons are not directly connected
(Mallick et al. 2012). It has been shown that GABA plays a significant role in
modulating these REM-ON and REM-OFF neurons for the regulation of REMS.
The GABA-ergic neurons have pre- and post-synaptic inputs on REM-ON and
REM-OFF neurons for the regulation of REMS. These cholinergic REM-ON,
noradrenaline (NA)-ergic REM-OFF, and the GABA-ergic neurons receive multi-
ple inputs; these may project onto themselves (Aghajanian et al. 1977; Jacobs 1986;
Mallick et al. 2012), among each other (Semba and Fibiger 1992; Jones 2004;
Mallick et al. 2012) or on to neurons in different regions of the brain performing
different functions (Mena-Segovia et al. 2002).
3 Withdrawal of Inhibition Induces REMS
For the generation of REMS, the LC-REM-OFF neurons cease activity, while at the
same time the REM-ON neurons in LDT/PPT increase firing. The GABA-ergic
inputs from substantia nigra (SN) act pre-synaptically on the inhibitory NA-ergic
terminals from the LC-REM-OFF neurons onto the REM-ON neurons in PPT. This
GABA-ergic input withdraws inhibition from PPT neurons causing disinhibition
(activation) resulting in initiation of REMS (Pal and Mallick 2009; Kumar et al. 2012;
Mallick et al. 2012). Currently there are three models explaining mechanism of REMS
generation (McCarley and Hobson 1975; Lu et al. 2006b; Luppi et al. 2013).
The SN and VTA primarily possess dopamine (DA)-ergic and GABA-ergic
neurons which project (Chinta and Andersen 2005) and receive inputs from dif-
ferent brain areas including LC (Ungerstedt 1971; Isaias et al. 2011) and PPT
(Beckstead et al. 1979; Semba and Fibiger 1992). DA is involved in abstract
emotions, which are affected in many conditions including in altered psychological
states (e.g., mood disorder, depression) and therefore, it has been popularly termed
the ‘feel-good chemical’. DA is also implicated in coordinating muscle activity and
movements, which are affected in Parkinson’s disease (PD) and REMS behavior
disorder (RBD). REMS is significantly compromised qualitatively as well as
quantitatively in most such disorders and there are reports indicating DA-ergic
modulation of REMS (Lima 2013). Initial reports suggested that the lesion of
DA-ergic neurons produced akinetic behavior however, the EEG sleep-waking
pattern was retained (Morgane and Stern 1974). In this chapter we review the
literature, which suggests DA-ergic modulation of REMS.
4 Dopamine
Arvid Carlsson was awarded the Nobel Prize in 2000 for the discovery of DA as
an independent neurotransmitter. Studies have shown its role in motor coordination
(Double and Crocker 1995; Hemsley and Crocker 1998), hallucination (Kataoka
and Ueno 2014; Kiferle et al. 2014), motivation (Salamone et al. 2003; Wise
2004), emotion (Salimpoor et al. 2011), memory (Denenberg et al. 2004;
Chowdhury et al. 2012), and reward (Yim and Mogenson 1980). DA plays an
important role in various disorders like PD (Politis et al. 2011; Gröger et al. 2014),
schizophrenia (Grace 1991; Knable and Weinberger 1997), narcolepsy (Hublin
et al. 1994; Rinne et al. 1996; MacFarlane et al. 1997) and depression (Willner
1983; Perugi et al. 2001); and in most of these conditions sleep and REMS are
affected (Boeve et al. 2007).
5 Location of DA-ergic Neurons
Dahlstrom and Fuxe (1964) described distribution of catecholaminergic neurons in

discrete brain areas in the rat brain. Based on formaldehyde histofluorescence
method twelve groups of catecholaminergic neurons (A1–A12) were identified,
which were distributed from medulla oblongata to hypothalamus. Later five addi-
tional cell groups, A13–A17, were added and these were found in diencephalon,
olfactory bulb and retina (Hokfelt et al. 1984). DA neurons are mostly located in A8
(retrorubral area), A9 (SN) and A10 (VTA) cell groups, while A12 (arcuate nucleus)
of hypothalamus contains less DA-ergic neurons (Chinta and Andersen 2005).
DA-ergic neurons in A9 and A10 regions are the primary source of DA in the
mammalian central nervous system (Stern and Morgane 1974). SN has been
anatomically divided into SN pars compacta (SNc) and SN pars reticulata (SNr).
DA-ergic neurons are packed in SNc, while they are scattered in SNr, which
contains relatively more GABA-ergic neurons. Chinta and Andersen (2005) and
Monti and Monti (2007) reported to and fro anatomical connections of the neurons
in SN and VTA. These regions also receive projections from LC and LDT/PPT
(Chinta and Andersen 2005).
6 Dopamine Receptors
Based on the differences in drug specificities and signaling mechanisms initially

two major subtypes of DA receptors were identified, namely D1 and D2.
Subsequently with the progress of molecular biology and molecular cloning tech-
niques, further subtypes of these receptors have been identified. D1-like subtypes
include D1 and D5, while D2-like subtypes include D2, D3 and D4 (Gingrich and
Caron 1993). Normally, D1-like receptors enhance the activity of adenylate cyclase
leading to Cyclic adenosine monophosphate (cAMP) production and depolarization
of the neurons leading to their excitation. D2-like receptors activate outward
potassium currents and inhibit inward calcium current leading to hyperpolarization
and inhibition of the neurons (Lee 1996; Wang et al. 2015).The mRNA of the
postsynaptic DA-receptors is differentially expressed in different regions in the
central nervous system in rats. In LC and PPT while the expressions of D1 and D2
receptor-mRNA have been reported, D3, D4 and D5 receptor-mRNA are absent
(Civelli et al. 1993; Mansour and Watson 1995; Meador-Woodruff 1995;
Lachowicz and Sibley 1997; Missale et al. 1998). DA-ergic neurons in SN and
VTA do not express D1 and D5 receptor-mRNA (Monti and Monti 2007). D2
receptors are largely expressed on cell bodies and dendrites of SN and VTA neu-
rons where these serve as autoreceptors (Sesack et al. 1994; Cragg and Greenfield
1997; Tepper et al. 1997). D3 receptors are expressed in moderate-to-low levels in
SN and VTA neurons which are presumed to be autoreceptors, whereas D4
receptors are present in low level (Mansour and Watson 1995; Meador-Woodruff
1995; Missale et al. 1998).The genes encoding G-protein coupled receptors are
generally intronless; however, D2 receptors are an exception and contain multiple
introns. Consequently, there is alternate splicing giving rise to two variants of D2
receptors, D2-long (D2-L) and D2-short (D2-S); the former has an additional
29-amino acid insert. Recently it has been proposed that D2-L and D2-S represent
post-synaptic and D2-S pre-synaptic autoreceptors (Usiello et al. 2000).
7 Intrinsic Regulation of Firing of DA-ergic Neurons—

Role of Autoreceptors
Several studies showed the presence of autoregulatory mechanism for release of

DA, which is mediated by presynaptic DA autoreceptors. In addition to the soma,
the dendrites of the DA-ergic neurons in the VTA and SN contain tyrosine
hydroxylase (TH), the rate-limiting enzyme in DA synthesis pathway (Bayer and
Pickel 1990; Nirenberg et al. 1996). DA is stored and released from
somato-dendritic regions of the DA-ergic neurons of the SN and VTA (Bjorklund
and Lindvall 1975; Geffen et al. 1976; Nieoullon et al. 1977; Cheramy et al. 1981).
Somato-dendritic release of DA from SN is dependent on extracellular Ca++ con-
centration that causes activation of voltage-dependent Ca++ channels. It is inde-
pendent of the status of voltage-dependent Na+-channels (Rice et al. 1997) and is
not mediated by reversal of the DA uptake transporter (DAT) (Cragg et al. 1997).
Furthermore, investigations using a number of different methods have shown that
somato-dendritic DA release in the VTA and SN is altered under different behav-
ioral and pharmacological conditions. This local DA release provides a potent
auto-inhibitory role in the VTA and SN by decreasing DA cell firing rate via
activation of D2 receptors. Intra-nigral delivery of amphetamine (DA-agonist)

decreases the firing of nigrostriatal neurons, while local application of haloperidol
(DA-antagonist) increases the activity of these neurons (Groves 1975; Aghajanian
and Bunney 1977). Activation of the DA-receptors in the SN by dendritic release of
DA may serve as an auto-inhibitor and thereby decrease striatal DA release
(Cheramy et al. 1981). The reduction in DA-ergic cell firing (Aghajanian and
Bunney 1977), 3H-DA release in the striatum (Nieoullon et al. 1977) after acti-
vation of the DA-receptor located in the SN and the reversal of these inhibitory
actions by neuroleptics are consistent with this hypothesis. These data therefore
demonstrate a potent auto-inhibitory role for DA within the nigro-striatal and
mesolimbic DA system.
8 DA in Depression
DA-ergic system has been reported to play an important role in modulation of the
pathophysiology of depression (Randrup and Braestrup 1977; Willner 1983).
Reduced behavioral activity for specific rewards has been correlated with decreased
level of DA in the nucleus accumbens in rodents (Salamone et al. 1999; Neill et al.
2002). Different DA-ergic agonists, e.g., piribedil (Post et al. 1978), bromocriptine
(Theohar et al. 1981) and amphetamine (Silberman et al. 1981) have been shown to
have antidepressant effects. Several studies have reported that tricyclic antide-
pressants (TCAs) act through DA-ergic system (De Montis et al. 1990; Brown and
Gershon 1993) as evidenced by an increment of DA-ergic activity after long-term
treatment with these agents. For example, concentration of DA in the nucleus
accumbens increases after treatment with TCA or Fluoxetine (Ichikawa and Meltzer
1995). Chronic administration of TCA (1) enhances efficiency of apomorphine (DA
agonist) increasing locomotor activity and stereotyped behaviors (Maj et al. 1984),
and (2) increases DA release by amphetamine (Brown et al. 1991; Nomikos et al.
1991). The extracellular concentration of DA significantly increases in the striatum
and prefrontal cortex during locomotor activity and dark periods (Feenstra et al.
2000). Reduced level of DA has been correlated with depression-like symptoms
(Dunlop and Nemeroff 2007) when REMS is reported to increase (Palagini et al.
2013). Whereas REMS deprivation (REMSD) has been used as a treatment for
depression (Gillin 1983). Based on the existing literature we propose that normally
DA increases waking and physical activity and exerts modulatory or biasing effect
on REMS. Reduced level of DA may possibly induce depression and associated
symptoms including increased REMS. Antidepressants may improve symptoms in
these patients by increasing DA level.
Most depressed patients suffer from sleep disturbance. Depressed patients show
increased REMS and REMSD ameliorates symptoms in these patients at least for
some time. Thus, behavioral REMSD has also been effectively used as an
antidepressant (Gillin 1983) although the effects may not be long lasting. Depressed
patients may show altered EEG pattern, prolonged sleep latency, increased number
of intermittent awakenings, decreased NREMS, shortened REMS latency, increased
REMS frequency and duration. (Benca et al. 1997; Tsuno et al. 2005; Armitage
2007; Steiger 2007; David Nutt and Paterson 2008; Pillai et al. 2011).
Antidepressants may affect sleep architecture (e.g., reduction of REMS duration and
frequency and prolonged REMS onset) (Sandor and Shapiro 1994; Argyropoulos
and Wilson 2005; Tsuno et al. 2005; Wilson and Argyropoulos 2005; Steiger and
Kimura 2010). Thus, both NREMS and REMS are altered in depression and
antidepressants as well as DA-ergic agonists/antagonists modulate REMS, how-
ever, the relationship between their mechanism of action is unknown.
9 DA in Parkinson’s Disease
PD is a neurological disorder that affects motor coordination as a result of

degeneration of DA-ergic neurons in SN and VTA (Agid et al. 1987; Freeman
2015). SN neurons project to the striatum which is primarily involved in motor
coordination and VTA neurons project to the ventral striatum, amygdala, prefrontal
cortex and other basal forebrain areas which are involved in cognitive and affective
functions. Degeneration of neurons in SN reduces DA level in corpus striatum
(Ehringer and Hornykiewicz 1960). The REMS is significantly reduced in PD
patients (Hilker et al. 2003; Lima 2013; Frauscher and Hogl 2015).
10 DA and REMS Behavior Disorder
REMS behavior disorder (RBD) is characterized by vigorous muscle activity and

body (limb) movement and abnormally increased phasic or tonic electromyo-
graphic activity associated with unpleasant dreams during REMS (Schenck et al.
2002; Lima 2013; Olson et al. 2000). In RBD the overall sleep architecture is
normal with normal NREMS-REMS cycling and REMS percentage. However,
slow wave sleep and REMS density (number of eye movements per minute of
rapid eye movements [REMs]) may be increased (Schenck and Mahowald 1990;
Mahowald and Schenck 2000, 2011). A recent report documented the loss of the
physiological increase of REMS duration and REMs frequency across the night
(Arnaldi et al. 2016). Although the pathophysiology of RBD still remains unclear,
several associated findings e.g., decreased striatal DA-ergic terminals and trans-
porter, occasional improvement of idiopathic RBD by pramipexole (a D2–D3
receptor agonist), suggest involvement of the nigrostriatal DA-ergic pathway in
REMS regulation (Matheson and Saper 2003).
11 Involvement of DA-D1 Receptors in Sleep

and Wakefulness
Several studies have shown the role of DA in modulation of sleep including REMS
and wakefulness (Wauquier 1985; Ongini and Longo 1989) L-dopa or DA agonist
stimulation of DA-ergic pathway increases wakefulness and decreases REMS
(Monti 1979; Cianchetti et al. 1980; Monti et al. 1989). Systemic administration of
selective D1 receptor agonist SKF 38393 enhanced grooming in the rat (Molloy and
Waddington 1987) and induced EEG desynchronization as well as behavioral
arousal in both rabbits and rats (Ongini et al. 1985). On the other hand, selective D1
receptor antagonist SCH 23390 produced sedation in the monkey and the rabbit
(Ongini et al. 1985; Bo et al. 1988) and enhanced REMS duration (Trampus and
Ongini 1990). D1 receptor agonist suppressed the amount of REMS in a
dose-dependent manner and enhanced wakefulness, while D1-receptor antagonists
increased REMS (Trampus et al. 1991).
Administration of D2 receptor antagonist, haloperidol,increased total time spent
in NREMS, but not in REMS (Monti 1983). It has been reported that the
intracerebro-ventricular injection of R-(-) 3(3-hydroxy-phenyl-npropyl-piperidine
hydrochloride ((-)-3PPP), a specific agonist of DA autoreceptors (Hjorth et al. 1981)
enhanced behavioral and electrocorticographic (ECoG) sleep in a dose dependent
manner, and reduced locomotor activity in freely moving rats (Bagetta et al. 1987).
Apomorphine or bromocriptine (D2 agonist) caused biphasic effects; low doses
reduced wakefulness and enhanced NREMS and REMS, whereas higher doses
reversed the effects in the rats. Pergolide (D2/D3 agonist) also showed biphasic
effects on wakefulness and NREMS, however, REMS was decreased irrespective of
the amount of the drug administered (Monti et al. 1988). It is notable that apo-
morphine injected bilaterally into the VTA produced behavioral and ECoG sleep in a
dose-dependent manner in the rats. The effects of apomorphine were prevented if its
local application was preceded by microinjection of a low dose of selective presy-
naptic D2 receptor antagonist, sulpiride (Bagetta et al. 1988). A low dose of quin-
pirole, a D2 receptor agonist, decreased wakefulness and tended to increase NREMS
and REMS, whereas a higher dose increased wakefulness and reduced NREMS as
well as REMS in the rats (Monti et al. 1989). In another similar study it was observed
that under conditions of low arousal, intra-cerebro-ventricular administration of
quinpirole promoted wakefulness (Isaac and Berridge 2003). On the other hand, D2
receptor antagonist YM-09151-2 although increased NREMS, it suppressed REMS
(Monti et al. 1989). Using [3H] YM-09151-2 binding, Hamdi et al. (1993) reported
that loss of REMS in rats was associated with a significant increase in the density of
DA-D2 receptor in the striatum. Significant decrease in wakefulness and increased
NREMS and REMS has been reported in D2 receptor knockout mice. Based on their
findings the authors concluded that DA receptors are involved in wakefulness and
not in sleep homeostasis regulation (Qu et al. 2010). Thus, it appears that D2
receptor modulates wakefulness, NREMS and REMS; however, changes in their
relative proportion or cause and effect relationship needs to be studied.
12 DA-ergic System and REMS Regulation
Destruction of A9 and A10 neurons in cats showed reduced DA level and total lack
of behavioral arousal (Jones et al. 1973). By and large the firing patterns of DA
neurons did not show significant alterations during sleep and waking states, except
during orientation behavior (Steinfels et al. 1983). These findings led the authors to
infer that DA is responsible for waking. However, subsequently it was observed
that REMS was selectively suppressed in MPTP induced PD model in cats (Factor
et al. 1990). In addition to waking, NREMS and REMS were also disturbed in
patients where DA-ergic system was affected. There are several studies which
provide crucial information about the direct or indirect participation of SN and DA
in REMS regulation (Lena et al. 2005; Lima 2013). Studies have shown that
changes in the central DA-ergic synaptic transmission have been associated with
several neurodegenerative and psychiatric disorders, including PD, schizophrenia,
depression (Carlsson 1987; Greenwood et al. 2006; Lima 2013). Subsequently SN
neurons were shown to increase firing during REMS as compared to NREMS and
waking states (Datta et al. 1991; Maloney et al. 2002; Dahan et al. 2007). The
extracellular levels of DA in different brain areas remained significantly elevated
during waking (Feenstra et al. 2000) as well as during REMS (Lena et al. 2005).
These observations support the role of SN and VTA areas in REMS regulation as
opposed to earlier views to the contrary (Steinfels et al. 1983). Dzirasa and his
colleagues also reported that DA plays a role in REMS regulation and such regu-
lation is mediated via the DA-D2 receptor. Diminishing the DA tone in normal and
DAT-KO mice decreased REMS and such effects were prevented exclusively by
the DA-D2 agonist (Dzirasa et al. 2006). In other studies electrophysiological
findings demonstrated that DA-D2 antagonist produced dramatic reduction of
REMS during the rebound phase after REMSD. This study also demonstrated that
REMSD selectively over-expressed DA-D2 receptors (Lima et al. 2008). Thus,
findings from independent studies suggest that DA may be involved in waking and
REMS. Although behaviorally the two states are quite different, the EEG is
desynchronized in both these states. It is possible that (but there is no direct evi-
dence) DA may be involved in EEG desynchronization.
It is also known that SN and VTA contain DA-ergic as well as GABA-ergic
neurons and receive projections from PPT and LC (Semba and Fibiger 1992;
Steininger et al. 1992; Ichinohe et al. 2000). DA-ergic neurons in VTA are active
during REMS recovery following REMSD (Maloney et al. 2002). Lu et al. (2006a)
showed that DA-ergic neurons in the ventral periaqueductal gray matter (adjacent to
the dorsal raphe nucleus), which is anatomically and functionally different from
VTA, are specifically active during spontaneous or induced waking. Ibotenic acid
lesion of those neurons decreased waking and increased sleep, particularly the
REMS (Lu et al. 2006a). It is important to note that midbrain ventral lesions,
including those of the A10 area, induced rather opposite effects on waking,
NREMS and REMS (Rye 2004). On the other hand, the GABA-ergic neurons from
SN have been reported to inhibit the cholinergic neurons in the PPT (Saitoh et al.
2003). Activation of PPT was shown to regulate muscle atonia in decerebrate cats
(Lai and Siegel 1990; Takakusaki et al. 2003) and muscle atonia is a characteristic
sign of REMS. In subsequent studies it was observed that although electrical
stimulation was ineffective, chemical stimulation of SNr increased REMS (Pal and
Mallick 2009). Further studies showed that chemical stimulation effect of SNr could
be mediated by modulation of GABA-ergic receptors in PPT. These findings
suggest that GABA-ergic inputs from SNr act presynaptically on NA-ergic inhi-
bitory terminals on PPT neurons to disinhibit PPT REM-ON neurons and thereby
increasing REMS (Pal and Mallick 2009; Mallick et al. 2012). Based on the present
knowledge we propose a simplified diagram (Fig. 1) showing possible connections
of SN neurons with those in LC and PPT for the regulation of REMS in normal and
disordered state. Finally, it appears that although SN neurons modulate REMS, the
specific roles of DA-ergic and GABA-ergic neurons and their interaction in REMS
regulation need to be carefully investigated. It is possible that DA-ergic neurons
could be responsible for EEG desynchronization, during waking and REMS.
Fig. 1 DA-ergic modulation of REMS in health and diseases: a model

13 Conclusion
REMS is a unique state and is essential for life; its regulation is very complex. Our
knowledge about its regulation is far from satisfactory. It is affected in most of the
psycho-somatic and neurodegenerative disorders. In many such disorders the
DA-ergic system is affected, however, in such cases we do not yet understand the
cause and effect relationship. So far the major focus of investigation on the regu-
lation of REMS has been to understand the complex interactions among NA, ACh,
GABA and glutamate. It is time that more attention be given to the study of role of
DA-ergic system in REMS regulation.
Acknowledgments MAK and RKY received UGC fellowship. Research funding from Indian
funding agencies viz. DBT-BUILDER, PURSE II and UPOE-II under Institutional support and
individual support under J.C. Bose fellowship and UGC to BNM are acknowledged.
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Dopaminergic Transmission
and Wake-Promoting Effects of Central
Nervous System Stimulants
Ritchie E. Brown
Abstract Pharmacological agents which increase dopaminergic neurotransmission

by blocking dopamine re-uptake by the dopamine transporter (DAT), such as
cocaine, amphetamines and modafinil, are potent wake-promoting substances in
mammals and even in invertebrates such as Drosophila Melanogaster. In mammals,
the cell bodies of dopamine neurons controlling the sleep-wake cycle are located in
the midbrain and brainstem. Midbrain dopamine neurons express high levels of DAT
and play a key role in emotional arousal in response to rewarding and aversive
stimuli. They are strongly excited by wake-promoting neurotransmitters such as
acetylcholine and orexins/hypocretins. However, their mean firing rate does not
change across the sleep-wake cycle. In contrast, wake-active brainstem dopamine
neurons in the dorsal raphe/periaqueductal gray have low DAT levels and play a tonic
role in controlling wakefulness. Dopamine neurons increase arousal by inhibiting the
nucleus accumbens, by exciting wake-promoting basal forebrain cholinergic and
brainstem serotonin neurons and by inhibiting sleep-promoting neurons in the pre-
optic hypothalamus. Dopamine acts on D1 type (D1, D5) and D2-type (D2, D3, D4)
receptors. Both types are involved in promoting arousal but D2 receptors in the shell
of the nucleus accumbens appear to be particularly important. Dopamine D4 receptors
modulate the amplitude of cortical gamma band (30–80 Hz) oscillations important
for attention and inhibit GABAergic inputs from the globus pallidus to the thalamic
reticular nucleus. Dopaminergic agents are widely used in clinical practice to mod-
ulate alertness in sleep and other disorders involving disrupted cortical activation.
Thus, further work on their mechanism of action is warranted.
The dopaminergic neurotransmitter system is one of the most intensely investigated

in neuroscience due to its links to brain reward pathways, drug addiction,
Parkinson’s disease and schizophrenia. However, the mechanisms by which it
R.E. Brown (&)

In Vitro Neurophysiology Section, Laboratory of Neuroscience, Department of Psychiatry,
VA Boston Healthcare System and Harvard Medical School, VA Medical Center Brockton,
Research 116A 940 Belmont Street, Brockton, MA 02301, USA
e-mail: Ritchie_Brown@hms.harvard.edu

DOI 10.1007/978-3-319-46437-4_2
20 R.E. Brown
controls sleep and wakefulness remain somewhat mysterious, despite the common
use of dopaminergic agents in clinical practice to treat daytime sleepiness.
1 History of Dopaminergic Stimulants
Chewing the leaves of Erythroxylum coca has been practiced in South America for
thousands of years as a means to boost energy, suppress sleep, inhibit appetite and
combat altitude sickness (Streatfeild 2001). When combined with an alkali, the
leaves of this plant release a low level of a natural stimulant, which has only been
known to us in the West since the 1504 report of the Spanish explorer, Amerigo
Vespucci (Streatfeild 2001). The main active ingredient, cocaine, was isolated in
Goettingen, Germany by Albert Niemann in 1859 and soon became the toast of
Europe and America, being incorporated into popular beverages such as Vin
Mariani and Coca-cola (Streatfeild 2001). Many prominent figures espoused its
wondrous properties, most notably, Sigmund Freud. Later, its addictive properties
and negative cardiovascular effects became more widely known, leading to its
removal from Coca-Cola and its classification as a restricted drug (Streatfeild 2001).
Amphetamine derivatives occur naturally in plants such as Khat, a plant used in
the Middle East as a stimulant for hundreds of years (Rushby 1999). Amphetamine
itself was first synthesized in 1887 but was not widely used until the 1930s when it
was introduced into the Benzedrine inhaler to treat asthma (Boutrel and Koob
2004). Amphetamines have been and are still being used in military settings to keep
soldiers awake, as well as for various medical uses (Boutrel and Koob 2004).
The most recently introduced of the psychostimulants, modafinil, was introduced
as a wake-promoting compound to treat narcolepsy in France in 1988 and was
approved by the FDA in the United States in 1998 (Wisor 2013). Unlike cocaine
and amphetamines it does not have a strong abuse potential and a pronounced sleep
rebound is not observed following its use.
The dramatic effects of drugs such as cocaine, amphetamine-like compounds and
modafinil on mood and arousal have been used and abused by many different
societies around the world. However, it is only in the past 50 or so years that we
have gained a better understanding of their effects on the brain and their potential
for treating disorders of arousal. Here I summarize our current state-of knowledge
of this exciting topic.
2 Psychostimulants Promote Dopaminergic

Neurotransmission
Biochemical studies in the 1960s and 1970s identified the mechanisms underlying
the release and synthesis of the catecholamines (Axelrod 1971). The rate-limiting
enzyme in the synthesis of all the catecholamines (Dopamine, noradrenaline and
Dopaminergic Transmission and Wake-Promoting Effects … 21
adrenaline) is tyrosine hydroxylase (TyH), which converts L-tyrosine to L-DOPA.

The carboxyl group is removed from L-DOPA by the enzyme DOPA decarboxy-
lase to form dopamine. The action of dopamine is limited by reuptake into the
presynaptic terminal by a sodium and chloride dependent transport process medi-
ated by the dopamine transporter (DAT), as well as by other catecholamine
transporters.
Early biochemical studies suggested that cocaine and amphetamine inhibit the
reuptake of dopamine, noradrenaline and serotonin into nerve terminals. In addi-
tion, amphetamines affect the transport of monamines into synaptic vesicles. The
development of radioligands for DAT led to studies which showed that the binding
affinity of cocaine and amphetamine for DAT correlate well with their potencies in
eliciting self-administration (Ritz et al. 1987). Similarly, a comparison of the
potencies of inhibitors of dopamine and noradrenaline reuptake in inducing
wakefulness in normal and narcoleptic canines revealed a correlation between the
in vitro binding affinity for DAT but not the noradrenaline transporter (NAT),
suggesting that blockade of dopamine reuptake is the most important effect
(Nishino 1998). DAT inhibitors, including amphetamine and modafinil strongly
increased wakefulness whereas NAT inhibitors main action was to suppress REM
sleep. In a separate study in cats, the wake-promoting effect of amphetamine was
maintained in animals with lesions of the main noradrenaline cell group projecting
to the forebrain, the locus coeruleus (Jones et al. 1977).
The cloning of various neurotransmitter transporters, including the dopamine
transporter in 1991, led to the generation of DAT knockout-mice, allowing direct
testing of the hypothesis that DAT mediates the stimulant properties of these
compounds. DAT KO mice had a 100-fold increase in the time constant for
clearance of dopamine and did not respond to cocaine and amphetamine with an
increase in locomotion (Giros et al. 1996). Cocaine and amphetamine failed to
increase extracellular dopamine levels in these animals. Detailed sleep-wake
analysis showed that similar to the effect of psychostimulants, DAT knockout mice
had reduced non-REM sleep time and increased wakefulness independent of effects
on locomotor activity (Wisor et al. 2001). Furthermore, the wake-promoting effects
of metamphetamine, modafinil and a selective DAT blocker were abolished, con-
firming that DAT inhibition is their primary mechanism of action in increasing
arousal (Wisor et al. 2001). However it should be noted that both dopamine D1 and
D2 receptors, which are strongly implicated in the wake-promoting actions of the
dopamine system (see below) are reduced by about 50 % in the ventral midbrain
and striatum of DAT KO mice (Giros et al. 1996).
Modafinil is often described as a novel wake-promoting compound, in particular
because its use does not lead to a pronounced sleep rebound, when compared with
other psychostimulants acting on the dopaminergic system. Modafinil is a selective
blocker of DAT but has a low affinity, resulting in only slow increases in extra-
cellular dopamine, when compared to amphetamines or cocaine, likely explaining
its low abuse potential (Wisor 2013). Unlike amphetamines, Modafinil increases
Fos expression, a marker of neuronal activity, in orexin/hypocretin neurons
(Scammell et al. 2000) and in a poorly defined anterior hypothalamic area (Lin et al.
22 R.E. Brown
1996). Wisor and colleagues tested the effect of amphetamine and modafinil in a
strain of narcoleptic dogs which have a defective orexin/hypocretin type II receptor
and in dopamine transporter knock-out mice (Wisor et al. 2001). The
wake-promoting effects of these compounds were maintained in the narcoleptic
dogs, consistent with their effectiveness in promoting wakefulness in narcoleptic
humans with reduced levels of orexin/hypocretins. Thus, despite the increase in Fos
activity in orexin/hypocretin neurons in normal animals, the wake-promoting effect
does not depend on these neurons. Similarly, the effectiveness of modafinil is
maintained in mice lacking neuronal histamine due to knockout of the synthesizing
enzyme, histidine decarboxylase (Parmentier et al. 2007).
Thus, although, these substances affect several different neurotransmitter sys-
tems, the main wake-promoting effect of all the psychostimulants appears to be due
to the enhanced release of dopamine.
3 Location of Dopaminergic Cell Groups Controlling

Arousal
The potent wake-promoting action of cocaine, amphetamines and modafinil and

their common site of action in increasing dopaminergic neurotransmission sug-
gested that the endogeneous dopamine systems of the brain play an important role
in the control of wakefulness. Increased levels of catecholamines, including
dopamine, correlate with increased wakefulness, whereas reduction of their levels
promotes sleep (Monti and Jantos 2008). Depletion of catecholamines and sero-
tonin by application of the alkaloid, reserpine, which binds to presynaptic vesicles
containing these neurotransmitters and prevents their refilling, or inhibition of the
synthesis of catecholamines with a-methyl para tyrosine produces an increase in
sleepiness (Meyers et al. 2011) whereas drugs that enhance the extracellular con-
centration of catecholamines by enhancing release or blocking reuptake increase
wakefulness. Similarly, wakefulness is enhanced in dopamine transporter knock-out
mice (Wisor et al. 2001).
The localization of catecholamine neurons was facilitated by the development of
the Falck-Hillarp staining technique which allowed visualization of their location
based on the chemical reaction between catecholamines and formaldehyde, leading
to cyclization of the catecholamines and the formation of strongly fluorescent
products (Carlsson et al. 1962). Dopaminergic neurons were found in many dif-
ferent parts of the brain (A8–A16 cell groups). The largest groups of dopamine
neurons are present in two adjacent midbrain regions, the substantia nigra (A9,
projecting to the dorsal striatum) and ventral tegmental area (A10, projecting to the
frontal cortex and ventral striatum = nucleus accumbens). In fact, 80 % of brain
dopamine is found in the striatum. An extension of the A10 group is found inter-
mingled with serotonin neurons in the ventral periaqueductal gray/dorsal raphe
region. This region appears to have different properties from the A9/A10 cell
groups and constitutes a wake-active, wake promoting cell group (Lu et al. 2006).
Several groups of dopamine neurons are located in the hypothalamus (A11–A15)
but little is known about them with regards to control of the sleep-wake cycle. One
study suggested increased activity of the A11 cell group during REM sleep
deprivation suggesting they are wake-active (Leger et al. 2010). Dopamine-
containing neurons are also located in the retina and olfactory bulb.
Many studies of the dopaminergic system are performed in rodents. However, it
should be noted that while rodent dopamine systems closely resemble those in
primates, there are also differences which may impact the mechanism by which
dopamine affects arousal. In particular, in rodents there is only a scant dopaminergic
innervation of the thalamus, but this innervation is much more pronounced in
monkeys and humans, particularly amongst the mediodorsal and the midline nuclei
which participate in the dorsal arm of the ascending reticular activating system
(Sanchez-Gonzalez et al. 2005). In primates the dopaminergic innervation of the
thalamus is comparable to dopaminergic innervation of cortex (Sanchez-Gonzalez
et al. 2005). Notably, the dopamine transporter, DAT, is not expressed by all
dopamine neurons equally. High levels of mRNA are seen in the substantia nigra
and ventral tegmental area dopamine neurons whereas high levels of DAT protein
are noted in the projection targets in the dorsal and ventral striatum but low levels
are seen in dopamine neurons outside the midbrain (Cerruti et al. 1993; Ciliax
et al. 1995, 1999). Thus, midbrain dopamine neurons and their striatal targets are
likely to mediate the arousal promoting effects of psychostimulants which act to
inhibit DAT.
4 Midbrain Dopamine Neurons Increase Arousal

in Response to Behaviorally Relevant Stimuli
Large, non-specific, electrolytic lesions of midbrain dopamine neurons and sur-

rounding areas/fiber bundles dramatically reduced arousal (Jones et al. 1973).
However, single-unit recordings from the substantia nigra (SN) and ventral
tegmental area (VTA) revealed that their average firing rate did not change across
the sleep-wake cycle (Steinfels et al. 1983; Miller et al. 1983). In apparent conflict
with these electrophysiological findings, microdialysis measurements of extracel-
lular dopamine in the medial prefrontal cortex and nucleus accumbens revealed
higher levels during wakefulness and REM sleep (Lena et al. 2005). In contrast to
the other aminergic neurons, dopamine neurons have the ability to fire bursts of
action potentials, which enhance neurotransmitter release in target areas and are
normally triggered in the presence of external cues signaling unexpected rewards
(e.g. food) (Schultz 1998). Thus, in freely behaving animals VTA dopamine neu-
rons likely fire more bursts during waking resulting in increased release of dopa-
mine in target areas such as the nucleus accumbens and prefrontal cortex. VTA
dopamine neurons also fire more in bursts during REM sleep (Dahan et al. 2007).
24 R.E. Brown
Very recently, in vivo calcium imaging from VTA dopaminergic neurons

demonstrated arousal-related changes in activity which are consistent with
increased burst discharge during waking and REM sleep, and which anticipated
changes in state (Eban-Rothschild et al. 2016). Furthermore, selective optogenetic
or chemogenetic of VTA dopaminergic neurons or their terminals in the nucleus
accumbens strongly increased wakefulness, whereas cell-body inhibition promoted
sleep and sleep-associated nest building (Eban-Rothschild et al. 2016). Inhibition of
VTA dopaminergic neurons prevented the increase in wakefulness produced by
rewarding or aversive stimuli.
Consistent with a role in emotional arousal, VTA neurons are excited by several
different neurotransmitters and neuromodulators which promote arousal (Korotkova
et al. 2003, 2006). VTA dopamine neurons are strongly excited by cholinergic
brainstem neurons via activation of nicotinic and muscarinic M5 receptors (Yeomans
and Baptista 1997; Yeomans et al. 2001; Pidoplichko et al. 1997). Activation of these
receptors increases bursting and plays a role in reward processes/addiction. Likewise,
we found in vitro that the wake promoting neuropeptides, the orexins/hypocretins,
increase the mean firing rate and bursting of VTA dopamine neurons and neighboring
GABAergic neurons (Korotkova et al. 2003). Orexin/hypocretin activation of VTA
dopamine neurons has been implicated in reinstatement of drug seeking behavior
(Boutrel et al. 2005). Other neurotransmitters involved in stress and emotional
arousal such as corticotrophin releasing factor and substance P, also excited VTA
dopamine neurons (Korotkova et al. 2006).
5 Brainstem Dopaminergic Neurons Have Increased

Activity During Wakefulness
In contrast to VTA and SN dopamine neurons, dopaminergic neurons in the ventral

periaqueductal gray(vPAG)/dorsal raphe region of the brainstem appear to have tonic
state-dependent variations in their activity; these dopaminergic neurons show
increased activity of the immediate-early gene product, Fos, during waking when
compared to sleep (Lu et al. 2006). Selective lesioning of these neurons by injections
of 6-hydroxydopamine, resulted in 63 % cell loss whereas non-selective lesions with
ibotenic acid were associated with 80 % cell loss. Both of these procedures caused a
marked (>20 %) reduction in 24 h amounts of wakefulness, the extent of which was
correlated with loss of dopamine neurons (Lu et al. 2006). In contrast, lesions of the
serotonergic neurons in this area with 5,7-dihydroxytryptamine, resulting in 80 %
loss of serotonin neurons did not affect 24 h amounts of sleep and waking. In fact, the
effect of lesion of vPAG dopaminergic neurons on total 24 h amounts of wakefulness
was larger than that seen with lesions of aminergic, cholinergic or orexin/hypocretin
neurons (Blanco-Centurion et al. 2007; Gerashchenko et al. 2003).
Tracing studies showed that dopaminergic vPAG neurons project to and receive
inputs from other parts of the sleep-wake circuitry such as the basal forebrain,
midline thalamus and the sleep-active VLPO neurons (Lu et al. 2006). Recent
in vitro electrophysiological recordings from these neurons showed that they have
similar intrinsic membrane properties as VTA dopamine neurons, including broad
action potentials and hyperpolarization-activated cation currents (Dougalis et al.
2012). Information on the neurotransmitter regulation of these neurons, which
might help explain their putative state-dependent firing is lacking at present, as are
in vivo electrophysiological recordings from these neurons correlating their dis-
charge with changes in behavioral state. In contrast to dopamine neurons in the SN
and VTA they exhibit low levels of DAT (Ciliax et al. 1995, 1999), suggesting that
they play a less prominent role in the arousing effects of psychostimulants.
6 Effector Mechanisms of Dopaminergic Control

of Arousal in Mammals
Neurotransmitters and neuromodulators exert their effects on their targets by

binding to specific receptor proteins and thereby leading to the opening or closing
of ion channels. In the case of dopamine, the five known receptors (D1–D5) are
metabotropic, meaning that they are coupled to guanosine-triphosphate (GTP)-
hydrolysing proteins (G-proteins) and affect ion channels indirectly. D1/D5 dopa-
mine receptors are coupled to the Gs, and the related Golf, G-proteins, the alpha
subunit of which stimulates the activity of adenylyl cyclase, and affects ion chan-
nels by increasing the activity of cyclic adenosine monophosphate (AMP)-depen-
dent protein kinases. D2/3/4 receptors couple to Gi/o proteins, the alpha-subunit of
which inhibits adenylyl cyclase. In addition, the bc subunits of these G-proteins can
directly bind to ion channels and affect their activity. Other effects are mediated
through modulation of synaptic transmission. Evidence supports a role for both D1-
like and D2-like receptors in dopaminergic promotion of wakefulness, but the D2
receptor appears particularly important in mammals. High doses of D1 and D2
receptor agonists increase wakefulness although low doses of D2 agonists may
cause the reverse effect, presumably due to activation of autoreceptors on dopamine
cell bodies and axon terminals (Monti and Monti 2007). D2 receptor knockout mice
exhibit a significant decrease in waking amounts due to a shorter wake bout
duration and a concomitant increase in sleep (Qu et al. 2010).
Where do D1 and D2 receptors act to promote arousal? Several lines of evidence
including recent optogenetic/chemogenetic experiments (Eban-Rothschild et al.
2016) suggest that the nucleus accumbens is a sleep promoting region and that
dopamine promotes arousal though inhibition of this area, although the downstream
mechanisms which mediate this effect are unclear. Lesions of the nucleus accumbens
increase wakefulness and reduce the duration of non-REM sleep bouts (Qiu et al.
2010). Local amphetamine injections in the vicinity of the nucleus accumbens and
medial septum/preoptic area causes arousal in the rat (Berridge et al. 1999) and the
wake promoting effects of modafinil are blocked by lesions of the accumbens core
26 R.E. Brown
region (Qiu et al. 2012). The nucleus accumbens contains high levels of both D2 and
adenosine A2a receptors, located on the somata and excitatory afferents to enkephalin
containing neurons projecting to the ventral pallidum and lateral hypothalamus
(Zhang et al. 2013). These two receptors have opposite effects on intracellular
signaling and sleep-wake behavior. A2a receptors stimulate adenylyl cyclase,
whereas activation of D2 receptors inhibits this signaling pathway. A2a receptors
promote sleep since antagonism of these receptors by caffeine promotes wakeful-
ness, an effect dependent on the nucleus accumbens (Lazarus et al. 2011). In con-
trast, D2 receptors inhibit adenylyl cyclase and promote arousal. Injection of a D2/D3
receptor agonist into the nucleus accumbens increased wakefulness, whereas an
antagonist increased sleep (Barik and de Beaurepaire 2005). These two receptors
have important functional interactions such that blockade or inhibition of one sub-
type affects the expression of the other subtype (Salmi et al. 2005), likely explaining
the enhanced response to caffeine in DAT knockouts which have reduced D2
receptors. One interesting feature of the nucleus accumbens is that it expresses
particularly high levels of dopamine D3 receptors, although to date the role of these
receptors in the control of sleep-wake has not been investigated in any detail.
In addition to the nucleus accumbens, other brain areas may contribute to the
wake-promoting effects of dopamine. In the dorsal raphe, activation of normally inhi-
bitory postsynaptic D2 receptors causes neuronal excitation via opening of non-selective
cation channels (Haj-Dahmane2001). In addition, at high concentrations, as will be
produced by psychostimulants, dopamine can act at adrenergic receptors. In vitro,
dopamine inhibits the activity of sleep-active melanin-concentrating hormone neurons
in the hypothalamus (Alberto et al.2011) and REM-active dorsal subcoeruleus nucleus
(Yang et al.2014) via a2 adrenoceptors. Surprisingly, in vitro studies also report that
dopamine inhibits orexin/hypocretin neurons in the hypothalamus, either via activation
of a2 receptors (Yamanaka et al.2006) or via activation of D2 dopamine receptors (Li
and van den Pol 2005), an effect which should promote sleep.
Less is known about the location of D1 receptors which mediate the arousal
effects of dopamine in mammals. A preliminary in vitro study identified excitatory
effects of dopamine on basal forebrain cholinergic neurons (Arrigoni and Saper
2003). Dopamine increased firing rate, caused depolarization and decreased after-
hyperpolarizations. These effects were mimicked by a D1 receptor agonist.
Dopamine D1 receptors are also highly expressed in the dorsal and ventral striatum
‘direct pathway’ neurons which project to the internal segment of the globus pal-
lidus and substantia nigra pars reticulata and release substance P.
Both D1 and D2 receptors are required for the arousing effects of modafinil (Qu
et al. 2008). Systemic administration of a D1 receptor antagonist (SCH23390,
30 µg/kg) or a D2 receptor antagonist (raclopride, 2 mg/kg) prior to low doses (22.5
or 45 mg/kg) of modafinil, completely blocked the arousing effect in wild-type
mice. At high doses (90 or 180 mg/kg) of modafinil, the effect was not blocked by
the D1 receptor antagonist and was only partly blocked by raclopride, suggesting
additional mechanisms mediate the effect at these doses. Modafinil-induced arousal
was blunted in D2 receptor knockout mice and the effect was completely blocked by
pretreatment with SCH23390.
7 Dopaminergic Control of Arousal in Drosophila
Dopaminergic neurotransmission not only regulates arousal in vertebrates but even

in simpler animals such as the fruit fly, Drosophila melanogaster (Shaw et al. 2000;
Hendricks et al. 2000). Flies have active and inactive (rest) periods which resemble
mammalian wake and sleep periods. As in mammals, waking is increased by
stimulants in Drosophila. Administration of methamphetamine (Andretic et al.
2005) or cocaine (Lebestky et al. 2009) increases wakefulness by increasing the
duration of waking bouts and counteracts the effect of sleep deprivation. Mutant
flies (fumin, fmn) with autosomal recessive mutations resulting in deletions in the
Drosophila homologue of DAT, leading to loss of function, have high levels of
activity, reduced sleep and lack a homeostatic sleep response (Kume et al. 2005).
Conversely, flies lacking the synthesizing enzyme for dopamine, tyrosine hydrox-
ylase, in the central nervous system have reduced arousal and increased sleep
(Riemensperger et al. 2011), as do flies exposed to an inhibitor of TH (Andretic
et al. 2005). Dopamine receptors in flies fall into similar categories as in mammals
i.e. D1-like and D2-like. There are two D1-like receptors (DA1/DopR and DopR2)
and a D2-like receptor (D2R). Flies lacking the dopamine D1 receptor have reduced
arousal (Lebestky et al. 2009) and are implicated in the response to sleep depri-
vation. Flies treated with the D2R agonist, bromocriptine, showed increased noc-
turnal locomotor activity which was inhibited in D2R knockouts (Lee et al. 2013).
Thus, both D1-like and D2-like receptors have been implicated in the control of
arousal in flies.
Sleep has been hypothesized to reflect a compensatory response to synaptic
potentiation occurring during waking (synaptic homeostasis hypothesis) (Tononi
and Cirelli 2003) and experiments in Drosophila have provided structural evidence
which supports this hypothesis (Bushey et al. 2011). In Drosophila, the intensity of
social experience during waking modified sleep need and architecture. This
response was dependent on dopaminergic and cyclic AMP signaling pathways,
consistent with evidence linking these pathways to long-term potentiation and
memory formation in other species (Ganguly-Fitzgerald et al. 2006). More
fine-grained analysis of the effect of activation of the dopaminergic system revealed
that activation of dopamine D1 receptors in the mushroom bodies, a region
implicated in learning, rescued sleep-loss induced learning impairments in an
aversive phototaxic suppression task (Seugnet et al. 2008). Separate from the
dopamine effect on the mushroom bodies, two recent studies identified a
dopaminergic projection to the dorsal fan-shaped body, and acting on DopR/DA1,
as being key mediators of dopamine control of arousal (Ueno et al. 2012; Liu et al.
2012). In contrast to mammals, activation of the DA1 receptor causes neural
inhibition, consistent with other experiments which suggest that the dorsal
fan-shaped body is a sleep-promoting region (Donlea et al. 2011).
28 R.E. Brown
8 Effect of Sleep Deprivation on Dopaminergic

Neurotransmission
Sleep homeostasis refers to the process which increases the amount and intensity of
sleep following a period of extended wakefulness. Fly, rodent and human studies all
suggest that sleep deprivation affects dopaminergic neurotransmission. In
Drosophila, mutations in DAT, resulting in reduced dopamine clearance, showed a
greater sleep rebound following sleep deprivation (Greenspan et al. 2001). Effects
of dopamine on sleep homoestasis in this species appear to require downregulation
of A-type potassium channels of the Shaker family and upregulation of two-pore
leak potassium channels (Pimentel et al. 2016). In the basal forebrain of rats, levels
of dopamine metabolites are increased during SD (Zant et al. 2011). Sleep depri-
vation in humans was associated with a decrease in dopamine D2/D3 receptors in
the nucleus accumbens, which would be consistent with an increase in sleepiness, if
dopamine inhibits this sleep-promoting area via these receptors. In humans, there
are polymorphisms in DAT, associated with variable numbers of a 40 base pair
sequence, with 9 or 10 repeats being most common. 10 repeat allele homozygotes
have 15–20 % reduced DAT availability in the striatum when compared with
heterozygous and homozygous 9-repeat allele carries and show an increased
homeostatic response to sleep deprivation (increased NREM duration and intensity)
(Holst et al. 2014). Furthermore, 10 repeat carriers responded to the stimulating
effect of caffeine, whereas 9-repeat carriers did not. The altered homeostatic
response to sleep deprivation may involve D1-like receptors since homeostatic
regulation of sleep was unaltered in D2R KO mice (Qu et al. 2010).
Sleep loss impairs cognition in humans and animals (McCoy and Strecker 2011).
Dopaminergic stimulants counteract the negative effects of sleep deprivation on
cognitive performance in humans (Pigeau et al. 1995). Similarly in Drosophila,
activation of the dopaminergic system can counteract the effects of sleep loss
(Seugnet et al. 2008). This important action provides a rationale for the use of these
substances to treat sleep disorders causing excessive daytime sleepiness.
9 Dopaminergic Control of Theta, Beta and Gamma

Oscillations
Wakefulness in mammals is characterized by increased amplitude of EEG oscilla-

tions in the theta (4–8 Hz), beta (14–30 Hz) and gamma (30–80 Hz) ranges (Brown
et al. 2012). Administration of methylphenidate or amphetamine to rodents increases
hippocampal theta activity (Dzirasa et al. 2006). DAT KO mice show a pronounced
increase in hippocampal theta oscillations in response to exposure to novelty which
does not require an increase in locomotor activity (Dzirasa et al. 2006).
Methylphenidate increases beta activity in anesthetized rats (Chemali et al. 2012)
and cocaine increases beta activity in awake humans, as originally shown by the
EEG pioneer, Hans Berger (Herning et al. 1985). Early EEG analysis was restricted
to frequencies below 30 Hz i.e., excluded the gamma range. More recent studies
have shown that gamma oscillations are important for a variety of high-level cog-
nitive functions and are abnormal in diseases involving impaired cortical activity
such as schizophrenia (Woo et al. 2010). In vitro and in vivo data suggest a possible
role for dopamine D4 receptors in the control of gamma (30–80 Hz) oscillations,
consistent with their preferential location in fast-spiking parvalbumin-positive cor-
tical interneurons (Mrzljak et al. 1996) involved in generating gamma oscillations
(Sohal et al. 2009). In hippocampal slices a selective D4 agonist, PD168077,
increased gamma oscillation power, due to increased synchronization of fast-spiking
interneurons (Andersson et al. 2012). Similarly, systemic administration of a D4
agonist, A-412996, in vivo enhanced beta and gamma power in the hippocampus
and in several different neocortical areas (Kocsis et al. 2014). In humans, poly-
morphisms in both DAT and the D4 receptor have been linked to variation in gamma
power (Demiralp et al. 2007). In particular the 10/10 genotype of DAT, which
reduces DAT expression and thereby increases extracellular dopamine, enhances
gamma band responses to target auditory stimuli. Together, these studies demon-
strate that in addition to promoting wakefulness, activation of the dopaminergic
system promotes higher-frequency oscillations required for cognition.
10 Use of Dopaminergic Stimulants to Increase

Alertness/Arousal in Sleep Disorders, Disorders
of Cortical Activation and Anesthesia
Although they have significant cardiovascular side effects, dopaminergic stimulants

may be useful clinically to treat sleep disorders and other conditions involving
impaired arousal.
Narcolepsy. Almost all cases of human narcolepsy result from degeneration of
orexin/hypocretin neurons in the hypothalamus (Taheri et al. 2002). Orexin neurons
densely innervate the VTA dopamine neurons (Peyron et al. 1998) and orexins have
a potent excitatory effect on both dopamine and GABAergic VTA neurons in vitro
(Korotkova et al. 2003, 2006). Thus, loss of these excitatory effects may contribute
to excessive daytime sleepiness in this disorder. In contrast, orexins do not affect
substantia nigra dopamine neurons (Korotkova et al. 2002). Dopamine reuptake
inhibitors promote wakefulness in narcoleptic canines (Nishino et al. 1998) and in
orexin knockout mice (Burgess et al. 2010). Modafinil and other psychostimulants
are prescribed to treat excessive daytime sleepiness in human narcolepsy. Modafinil
does not improve cataplexy, unlike inhibitors of the noradrenaline reuptake trans-
porter, an additional line of evidence suggesting that its arousal promoting prop-
erties result from effects on the dopamine system (Nishino and Mignot 1997).
Emergence from Anesthesia. In rodents, administration of methylphenidate
decreases the time to emerge from isofluorane (Solt et al. 2011) or propofol
30 R.E. Brown
anesthesia (Chemali et al. 2012). Similar effects are produced by application of the
D1 receptor agonist, chloro-APB (Taylor et al. 2013) or by electrical stimulation of
the VTA (Solt et al. 2014) but not by the D2 receptor agonist, quinpirole (Taylor
et al. 2013) or by electrical stimulation of the SN (Solt et al. 2014).
Methylphenidate, chloro-APB and electrical stimulation of the VTA all decrease
EEG delta activity but there are differences observed in other frequency bands with
methylphenidate causing a marked increase in theta and beta activity, which was
less marked or absent with the other two manipulations. Overall, it appears that
dopaminergic stimulants may be useful in hastening the recovery from anesthesia,
at least in animal models.
Vegetative state/minimally conscious state (VS/MCS). Alterations in arousal
and consciousness produced by general anesthesia resemble those observed in
patients in comatose or vegetative states (Brown et al. 2010). Similar to their effects
on anesthesia in animals models, dopaminergic stimulants have shown beneficial
effects in a small number of brain-damaged patients, although appropriate diag-
nostic criteria for VS/MCS were not always applied. Matsuda and colleagues tested
the effect of L-DOPA in a small group of VS/MCS patients (4 in VS and one in
MCS) who had been in these states for 3–22 months (Matsuda et al. 2005). All 5
patients had suffered a closed head injury in a traffic accident. Remarkably, fol-
lowing the beginning of L-DOPA treatment, this small group of patients showed
evidence of emergence from VS/MCS within 4 days–1.5 months, improved motor
symptoms, an ability to communicate or to use objects functionally and the ability
to obey simple verbal commands. However, in a study such as this without a control
group it is not possible to determine if recovery might have occurred without drug
treatment. Similar to the effect of L-DOPA, the dopaminergic receptor agonist,
Bromocriptine, a potent agonist at D2/D3 receptors, as well as several other
monoaminergic receptors, improved functional recovery in a group of 5 VS patients
(Passler and Riggs 2001).
Another drug which acts on the dopamine system is amantadine. Amantadine
blocks dopamine re-uptake and facilitates dopamine synthesis. In addition, it acts as
an NMDA receptor antagonist. In an initial study in one patient who had been in a
MCS for 5 months, amantadine had a dose-dependent effect on arousal as assessed
by coma-near coma scores (Zafonte et al. 1998). More recently, in a
placebo-controlled trial, amantadine accelerated the pace of functional recovery in
patients with post-traumatic disorders of consciousness (Giacino et al. 2012). This
is currently the only pharmacological agent which has been shown to be effective in
improving clinical and motor function in VS/MCS in a well controlled clinical trial.
In one patient, a fast recovery from MCS was observed following administration
of the dopamine receptor agonist apomorphine (Fridman et al. 2009), somewhat
reminscent of the effect of dopaminergic agents in promoting emergence from
anesthesia. Apomorphine acts on both D1-like and D2-like receptors at nanomolar
concentrations. This patient showed improvements in consciousness and respon-
siveness within a few hours on the first day of administration of apomorphine,
104 days post-injury, although the patient had previously been unsuccessfully
treated with two other dopaminergic stimulants, methylphenidate and bromocriptine.
Parkinson’s disease is characterized by loss of dopamine neurons in the sub-

stantia nigra and parts of the VTA. These patients suffer from daytime sleepiness
which is normalized by treatment with L-DOPA, and movement disorders during
sleep (Rye 2004a, b). However, dopamine neurons are not the only neurons to be
affected by this disease and in fact early degeneration of brainstem REM muscle
atonia neurons is thought to lead to REM sleep behavior disorder (RBD), which can
anticipate the later development of Parkinson’s (Boeve et al. 2001).
Schizophrenia. The dopaminergic system has long been implicated in
schizophrenia since classic neuroleptics are potent inhibitors of dopamine D2
receptors. In addition, the atypical antipsychotic, clozapine, has strong affinity for
dopamine D4 receptors (Van Tol et al. 1991). Schizophrenia is increasingly rec-
ognized as a disorder involving abberant cortical activation in the gamma frequency
(30–80 Hz) range in response to sensory stimuli and during cognitive tasks
(Uhlhaas and Singer 2010; Woo et al. 2010). Thus, it is of interest that activation of
the dopamine system promotes gamma oscillations. Dopamine D4 receptors also
inhibit the inhibitory inputs from the external segment of the globus pallidus to the
thalamic reticular nucleus (Govindaiah et al. 2010; Gasca-Martinez et al. 2010),
which in turn controls the level and pattern of activity of thalamic relay neurons,
including the midline and intralaminar neurons involved in control of arousal. Thus,
modulation of the dopaminergic system and in particular D4 receptors may be
beneficial in correcting gamma band abnormalities associated with cognitive dys-
function in this disorder.
11 Conclusions
Psychostimulants such as cocaine, amphetamine, methylphenidate and modafinil

increase arousal primarily by blocking the dopamine transporter located on midbrain
dopamine neurons projecting to the nucleus accumbens, thereby potentiating the
inhibitory effect of D2 receptor activation on striatopallidal neurons. The down-
stream effects of this inhibition of nucleus accumbens neurons to increase arousal are
still unclear but do not require orexin/hypocretin or histamine neurons. Additional
effects of psychostimulants to promote arousal, particularly at high concentrations,
result from activation of D1 receptors on striatal/accumbens neurons, D2 receptors on
dorsal raphe neurons and adrenergic effects on sleep-promoting neurons, either
through inhibition of noradrenaline uptake or through dopamine binding directly to
these receptors.
Physiological roles for the dopamine system to promote arousal appear to result
from a tonic action of vPAG dopamine neurons on several nodes of the sleep-wake
circuitry and emtional arousal mediated by VTA neuron projections to the nucleus
accumbens. In Drosophila, dopamine promotes arousal by inhibition via D1-like
receptors in the sleep-promoting dorsal fan-shaped body as well as D1-receptor
effects on the mushroom body regions involved in learning and memory.
32 R.E. Brown
Genetic variations in dopamine clearance affect sleepiness associated with pro-

longed wakefulness. Alterations in the availability of dopamine D2 receptors in the
nucleus accumbens following prolonged wakefulness may be involved in this
homeostatic regulation of sleepiness.
Dopaminergic stimulants effectively counteract this sleepiness and ameliorate
cognitive impairments associated with sleep deprivation in mammals and in
Drosophila, supporting the use of wake-promoting dopaminergic agents to treat
excessive daytime sleepiness in narcolepsy and Parkinson’s disease. Dopaminergic
agents can also increase arousal in anesthetized patients or brain damaged patients
with disorders of consciousness.
In addition to increasing wakefulness per se, activation of the dopaminergic
system increases the higher frequency EEG oscillations typical of this state.
Activation of dopamine D4 receptors, in particular increases gamma frequency
oscillations, likely via effects on fast-spiking cortical interneurons containing par-
valbumin and modulation of the activity of the thalamic reticular nucleus.
Modulation of this effect may be useful in treating gamma oscillation deficits in
schizophrenia and other disorders such as autism.
Study of the role of the dopaminergic system in arousal has the potential to better
inform our understanding of the brain control of wakefulness and lead to novel
stimulants to treat excessive daytime sleepiness, emergence from anesthesia and
disorders of cortical activation.
Acknowledgments This work was supported by the US Veterans Administration (Merit Award
I01BX001356) and by the US National Institutes of Health: NIMH R01 MH039683, R21
MH094803, NHLBI HL095491 and NINDS R21 NS093000. The contents of this review do not
represent the views of the U.S. Department of Veterans Affairs or the United States Government.
Conflicts of Interest
The author declares no competing financial interests.
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The Effects of Dopamine Receptor
Agonists on the Sleep-Wake Cycle
Andrea Herrera-Solís, Oscar Arias-Carrión, Andrea Sarro-Ramírez,

Mireille Salas-Crisóstomo and Eric Murillo-Rodríguez
Abstract Dopamine (DA), a neurotransmitter that regulates the sleep-wake cycle,

has been involved as a wake-promoting molecule. Moreover, the diversity of
neurobiological functions controlled by DA, including the sleep-wake cycle, are
mediated by the DA family, which comprises D1, D2, D3, D4 and D5 receptors.
From the pharmacological point of view, compounds that bind and activate DA
receptors are significant means for the study of mechanism of action of DA
controlling biological phenomena such as sleep. Here, we highlight the current
knowledge regarding the role of DA receptor agonist in sleep modulation.
Keywords Dopamine Sleep Wakefulness Dopamine receptors Animal

models
1 Introduction
Dopamine (DA)-containing neurons have been described in the substantia nigra and
ventral tegmental area, both wake-related brain areas (Jones 2005; Smith and
Kieval 2000). The neurons in these nuclei send projections to the striatum, basal
A. Herrera-Solís O. Arias-Carrión
Unidad de Trastornos del Movimiento y Sueño (TMS), Hospital General
Dr. Manuel Gea González, México D.F., Mexico
A. Sarro-Ramírez M. Salas-Crisóstomo E. Murillo-Rodríguez (&)
Laboratorio de Neurociencias Moleculares e Integrativas Escuela de Medicina,
División Ciencias de la Salud, Universidad Anáhuac Mayab, Mérida, Yucatán, Mexico
e-mail: eric.murillo@anahuac.mx
A. Sarro-Ramírez M. Salas-Crisóstomo E. Murillo-Rodríguez
Grupo de Investigación en Envejecimiento, División Ciencias de la Salud,
Universidad Anáhuac Mayab, Mérida, Yucatán, Mexico
E. Murillo-Rodríguez
Grupo de Investigación Desarrollos Tecnológicos para la Salud, División de Ingeniería
y Ciencias Exactas, Universidad Anáhuac Mayab, Mérida, Yucatán, Mexico

DOI 10.1007/978-3-319-46437-4_3
40 A. Herrera-Solís et al.
forebrain and cerebral cortex showing a higher electrophysiological activity during

arousal (Maloney et al. 2002; McGinty and Harper 1976; McGinty and Szymusiak
2005; Mirenowicz and Schultz 1996).
DA receptors belong to G protein-coupled receptors that are present in the
central nervous system (CNS) and activation of these receptors are mediated by DA
as the primary endogenous ligand(Moreira and Dalley 2015; Rangel-Barajas et al.
2015). The activation of DA receptors have been linked in modulation of several
neurobiological processes, such as cognition, learning and memory, motivation,
pleasure, and sleep (Beaulieu et al. 2015; Bodea and Blaess 2015; Boyd and
Mailman 2012; Inta et al. 2012; Rangel-Barajas et al. 2015; Savica and Benarroch
2014), DA receptors have been targeted as pharmacological key elements for
treatments, such as Parkinson’s disease (Bastide et al. 2015; Berthet and Bezard
2009; Fiorentini et al. 2013; Pich and Collo 2015).
The expansion of knowledge in this pharmacological area has increased
considerably in the last years, and it is a challenge to describe all the current
evidence regarding the role of DA receptors in sleep modulation. However, in this
chapter we highlight the current understanding of the role of DA agonists in the
control of the sleep-wake cycle.
2 The DA Receptor Family and Sleep Modulation
DA modulates several physiological functions via activation of its receptors which

include D1, D2, D3, D4 and D5 (Beaulieu et al. 2015; Boyd and Mailman 2012; see
Fig. 1). Several pharmacological studies have reported that activation/deactivation
of these receptors promote differential neurobiological outcomes (Arnsten et al.
2015; Coria-Avila et al. 2014; Fiorentini et al. 2013; Le Foll et al. 2014; Ramirez
and Smith 2014). In the following section, we discuss the role of agonists for DA
receptor family in sleep modulation.
3 D1 Receptor Agonists and Sleep Modulation
D1-like receptors are located at the postsynaptic side of the synaptic cleft and are
coupled to the G protein, Gsa and Golf(Beaulieu et al. 2015; Rangel-Barajas et al.
2015). Gsa activates adenylyl cyclase leading to an increase in the intracellular
concentration of cyclic adenosine monophosphate (cAMP) (Brust et al. 2015;
Cooper 2015). Most of the pharmacological studies of D1 receptor agonists in sleep
have reported as wake-promoter(Dzirasa et al. 2006; Monti et al. 1990; Monti and
Jantos 2008; Monti and Monti 2007; Trampus et al. 1993). In this regard, systemic
administration of D1 receptor agonist SKF38393 suppressed rapid eye movement
sleep (REMS) (Monti et al. 1990). Moreover, the D1 receptor agonist SKF38393
and A68930 increased wakefulness, and reduce REMS at a dose-dependent fashion
The Effects of Dopamine Receptor Agonists on the Sleep-Wake Cycle 41
Fig. 1 Dopamine (DA) is a

catecholamine that mediates
sleep by interacting with DA
cell surface receptors which
are metabotropic G-protein
coupled receptors (GPCRS)
that are classified into D1-like
and D2-like receptors based
upon their pharmacological,
physiological and
biochemical properties
(Trampus et al. 1991, 1993).Regarding this issue, Isaac and Berridge (2003)re-
ported that actions of centrally administered D1 receptor agonist, SKF-82958 (2.5
and 25 nmol) dose-dependently increased time spent awake and suppressed slow
wave sleep (SWS), and REMS in the 2 h immediately post-injection.
Furthermore, sleep disturbances as in restless legs syndrome (RLS) are treated
using DA agonists such as rotigotine with selectivity for D1,D2 and D3 receptors.
For instance, if administered once a day using dosage of 0.5–4 mg/24 improved the
symptoms of RLS (Serafini et al. 2010). Similar results have been reported using
pramipexole (PPX) as therapy in an animal model and human studies of RLS. In
this regard, mice with the RLS were treated with PPX for a period of 28 and
84 days and they showed attenuated locomotor activities (Luo et al. 2011).Recently
it was demonstrated that selective D1 receptor agonist SKF38393 efficiently alle-
viated excessive daytime sleepiness and restored REM sleep in primate experi-
mental model of Parkinson’s disease (Hyacinthe et al. 2014).
4 D2 Receptor Agonists and Sleep Control
The D2-like family receptors are coupled to the G protein Gia, which directly
inhibits the formation of cAMP by inhibiting the enzyme adenylyl cyclase
(Beaulieu et al. 2015; Rangel-Barajas et al. 2015).
The bromocriptine, a D2 receptor agonist administered systemically at doses that
selectively stimulate DA auto-receptors, induced an increase in SWS and decreased
wakefulness in rats (Monti et al. 1990). In contrast, the injection of quinipirole (a D2
receptor agonist) in rats promoted opposite effects: at low doses it diminished
wakefulness whereas at higher doses promoted sleep (Monti et al. 1989).

Furthermore, the effects of RO 41-9067, a D2 receptor agonist, on sleep were
studied by Python et al. (1996). Animals that received RO 41-9067 showed a
dose-dependent increase in waking. Further studies have been developed showing
that D2 receptors also modulate sleep disturbances in RLS, and cabergoline, a D2
agonist showed a significant reduction of the number of periodic leg movements
(Stiasny et al. 2000) in RLS.
Another D2 receptor agonist, pramipexole reduces sleep latency and increases
total sleep duration in Parkinson’s disease and RLS (Micallef et al. 2009). Similar
results have been found after using ropinirole. Ferreira et al. (2002) reported that
ropinirole reduces time to sleep onset in humans. Moreover, the selective D2
agonist, piribedil behaves as a potent wake-promoting compound.
Electrophysiological findings have demonstrate that piribedil reduced REMS dur-
ing the rebound period after 96 h of REMS deprivation (Lima et al. 2008).
However, it has been reported that sleep attacks are present in patients with
Parkinson’s disease (PD) treated with piribedil (Gouraud et al. 2011).
Cabergoline also modulates sleep. Mice were given an intraperitoneal injection
of 0.3 mg/kg of cabergoline or vehicle before a control procedure of 1 h of sleep
deprivation, Later, cabergoline or vehicle was given 15 min before 1 h of restraint
stress. Results from this experiment showed that cabergoline blocked the ability of
restraint stress to increase amount of REMS (Jefferson et al. 2014).
5 D3 Receptor Agonists and Sleep-Wake Regulation
The data regarding the role of D3 receptor agonist on sleep modulation is limited.
However, it has been shown that administrations of D3 agonist pramipexole (10–
500 lg/kg) displays pharmacological properties on sleep modulation. For example,
the 30 lg/kg dose increased SWS and REMS, and reduced wakefulness (W),
whereas the 500 lg/kg dose enhanced waking time (Lagos et al. 1998). Moreover,
D3receptor agonists 7-OH-DPAT and quinelorane showed an awakening effect
(Barik and de Beaurepaire 2005). The opposite results have suggested that higher
doses might be activating D2 receptors.
6 D4 and D5 Receptor Agonists and Sleep
Surprisingly, no solid evidence is available regarding the role of either D4 or D5

receptor agonists on sleep modulation. The only data available reported the effects
of Ro 10-5824 and A-412997 on the sleep-wake states in rats. These data showed
increased waking and reduced non-REM (NREM) sleep duration in rats.
The NREM sleep onset latency was also delayed. However, only A-412997, but not
RO 10-5824 influenced REMS duration and onset (Nakazawa et al. 2015).
Fig. 2 Dopamine (DA) mediates sleep subgroups of DA receptors named D1, D2, D3, D4 and D5
or D1-like and D2-like. The D1-like receptor family includes D1 and D5 receptor subtypes, and the
D2-like family comprises D2, D3 and D4 subtypes. The D1-like receptors are coupled to stimulatory
G-proteins whereas D2-like receptors are coupled to inhibitory G-proteins. Activation of D1-like
receptors would increase activity of adenylcyclase while activation of D2-like receptors would
cause an opposite effect
On the other hand, rotigotine, a non-ergoline DA agonist at clinical doses also

binds to D5 receptors. This drug is used for treatment of PD and RLS and it has
been shown to improve total sleep time and diminish nocturnal motor symptoms in
PD patients (Liguori et al. 2015; Pagonabarraga et al. 2015). Further studies
however, are needed to characterize the pharmacological properties of D4/D5
receptor agonists on sleep modulation.
7 Conclusions
The dopaminergic agonists effects on sleep-wake cycle are complex and depend on
several factors such as dosage, affinity to different types of receptors, etc. (Fig. 2).
Most of the DA agonists were developed to treat PD and RLS in the last decade.
Pharmacological effects on sleep of activation mostly of D1 receptor agonists have
been reported showing a wake-promoting profile. Pharmaceutical advances have
allowed to explore the neurobiological role of new drugs that are aimed to bind to
DA receptor family. However, further evidence is needed to understand the role of
D4/D5 receptor agonists since limited data are available regarding this issue. The
mechanisms of action of DA receptors are not completely understood, and any
design for novel treatment of sleep disturbances will require further understanding
how different DA signaling pathways work.
Acknowledgments Oscar Arias-Carrión is supported by CONACYT-BMBF 2013 (Grant

208132). Eric Murillo-Rodríguez is supported by Escuela de Medicina, Universidad Anáhuac
Mayab.
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Functional Interactions Between
MCHergic and Dopaminergic Neurons:
Role in the Control of Wakefulness
and Sleep
Pablo Torterolo, Luciana Benedetto and Jaime M. Monti
Abstract Dopamine (DA) plays an important role in emotional arousal. In addi-

tion, recent studies have demonstrated that there is an increase in DAergic activity
both in the nucleus accumbens and prefrontal cortex during rapid-eye-movement
(REM) sleep; this DAergic activity has been involved in the generation of dreams.
The melanin-concentrating hormone (MCH) is a peptide with neuromodulatory
functions synthesized by neurons located in the postero-lateral hypothalamus and
incerto-hypothalamic area. MCHergic neurons project throughout the central ner-
vous system, including the substantia nigra pars compacta and ventral tegmental
area, where DAergic neurons are located. MCH controls energy homeostasis, with a
main role in energy conservation. In agreement with the energy-conserving function
of sleep, MCH promotes sleep. In comparison to wakefulness (W), MCHergic
neurons increase their firing rate during non-REM (NREM) sleep and reach their
maximal rate during REM sleep. Although there is almost no direct information
regarding the interaction between MCHergic and DAergic neurons in the control of
W and sleep, indirect evidence strongly suggests an important interaction between
both systems in the control of these behavioral states. MCHergic fibers and
receptors are present in the DAergic mesocorticolimbic system, a key center for
activation and motivation. Furthermore, the absence of MCH leads to an increase in
DA release and the up-regulation of DA receptors that is known to facilitate the
generation of W. On the other hand, DA decreases the release of MCH; this fact
would also promote W. While both systems seem to have opposite effects in the
generation of W, they appear to have complementary roles in the regulation of
different aspects of REM sleep. In conclusion, although more experimental data is
needed, available evidence tends to indicate that functional interactions between the
P. Torterolo (&) L. Benedetto

Laboratorio de Neurobiología Del Sueño, Departamento de Fisiología,
Facultad de Medicina, Universidad de la República, General Flores 2125,
11800 Montevideo, Uruguay
e-mail: ptortero@fmed.edu.uy
J.M. Monti
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Hospital de Clínicas,
Universidad de la República, Montevideo, Uruguay

DOI 10.1007/978-3-319-46437-4_4
48 P. Torterolo et al.
MCHergic and DAergic systems play an important role in the control of behavioral
states.
Keywords Hypothalamus
Ventral tegmental area Substantia nigra

Melanin-concentrating hormone REM sleep
1 Synopsis of the Dopaminergic System
Details about dopamine (DA) and the DAergic system can be found in other
chapters of the book. Briefly, DA is a neurotransmitter with high clinical relevance,
since its reduction at striatal sites is related to the pathogeny of Parkinson’s disease
(Lima 2013). Moreover, DA is implicated in the mechanism of action of antipsy-
chotic drugs (Cooper et al. 1996). Although much of the attention has been given to
DA in locomotor activity, sensorimotor integration and motivation, DA plays also a
significant role in the regulation of sleep and wakefulness (W) (Monti and Monti
2007; Monti and Jantos 2008).
Molecular cloning techniques have enabled the characterization of two distinct
groups of DA receptors, D1-like and D2-like receptors (Meador-Woodruff 1994;
Lachowicz and Sibley 1997). The D1 subfamily includes the D1 and D5 receptors,
whereas the D2 subfamily comprises the D2, D3 and D4 receptors. The D1 and D2
receptors have a wider distribution and predominate in the central nervous system
(CNS) as compared with the D3 to D5 receptors. The D1 receptor is a postsynaptic
receptor that is coupled to adenylate cyclase, and its stimulation facilitates the
activity of the enzyme. DA receptors corresponding to the D2 subfamily are cou-
pled to the inhibition of adenylate cyclase. In addition, D2-like receptors increase
outward K + currents, inhibit inward Ca2+ currents, and modulate phosphoinosi-
tide metabolism. The D2 receptor has been characterized also on DAergic cell
bodies and dendrites in the substantia nigra pars compacta (SNc) and the ventral
tegmental area (VTA) (autoreceptor function).
The effects of DA released in the synaptic cleft are terminated in part by reuptake
through a membrane carrier. Alternatively, DA can be inactivated by the enzymes
monoamine oxidase type B (MAO-B) and catechol-O-methyltransferase (COMT)
(Cooper et al. 1996).
The DAergic neuronal system relevant to sleep and W is located in the upper
mesencephalon. One group of DAergic neurons is located in the SNc and project
towards the dorsal striatum. A second group of DAergic neurons arises in the VTA
and projects either to the limbic system [septal area, olfactory tubercle, nucleus
accumbens (NAc), amygdaloid complex and piriform cortex] or the cerebral cortex
(medial prefrontal, cingulate and entorhinal areas). D1 and D2 receptors are present
within these structures.
Additionally, Lu et al. (2006) recognized by means of Fos immunoreactivity
(a marker of neuronal activity) and neurochemical lesions a group of DAergic
Functional Interactions Between MCHergic and Dopaminergic … 49
neurons in the ventral periaqueductal gray (vPAG) that may also have a critical role
in the generation of W.
2 The Dopaminergic System and Sleep
In homoeothermic animals, sleep is divided into two main states: REM and
non-REM (NREM) sleep (Torterolo and Vanini 2010). NREM sleep is character-
ized by high voltage slow oscillations in the electroencephalogram
(EEG) associated with weak electromyographic (EMG) activity. During this state,
cognitive activity is scarce. During REM sleep, activity in the EEG is comparable to
W (high frequency and low voltage oscillations), and is associated with theta
rhythm in the hippocampus electrogram and muscle atonia. Dreams occur mostly
during REM sleep (Hobson 2009).
There is a reciprocal interaction between the DAergic neurons of the SNc/VTA
and other critical areas for W and REM sleep generation (Monti and Monti 2007).
These areas are the dorsal raphe nucleus (DR, serotonergic neurons), the locus
coeruleus (LC, noradrenergic neurons), the laterodorsal (LDT) and pedunculo-
pontine tegmental nuclei (PPT, cholinergic neurons), the tuberomammillary nucleus
of the hypothalamus (histaminergic neurons), the basal forebrain (BF, cholinergic,
glutamatergic and GABAergic neurons) and the postero-lateral hypothalamus
(hypocretinergic neurons). Hypocretinergic neurons are intermingled (but do not
co-localize) with the MCHergic neurons (Torterolo et al. 2006).
DAergic neurons of the VTA and SNc do not change their mean firing rate
across the sleep-wake cycle (Trulson et al. 1981; Miller et al. 1983; Trulson and
Preussler 1984; Trulson 1985). However, the temporal pattern of the discharge is
strongly modulated during the sleep-wake cycle. Accordingly, during W, DAergic
neurons discharge in burst in response to salient stimuli (Schultz et al. 1993). This
increase in bursting activity is accompanied by a substantial increase in DA
extracellular levels (Wightman and Robinson 2002). In this regard, microdialysis
studies by Lena et al. (2005) have shown that DA release is greater during W in
comparison to sleep both in the prefrontal cortex and NAc.
DAergic neurons do not modify their firing rate during REM sleep. However,
Dahan et al. (2007) demonstrated that there is a prominent burst firing increase in
VTA DAergic neurons during REM sleep, that resemble the bursting induced by
the consumption of palatable food. This is in line with previous findings that
described an increase in the number of Fos immunoreactive neurons during REM
sleep (Maloney et al. 2002). In addition, the release of DA both in the NAc and
prefrontal cortex increases during REM sleep in comparison to NREM sleep (Lena
et al. 2005). In this regards, DAergic VTA neurons participates in the promotion of
hippocampal theta rhythm, a prominent feature of REM sleep (Orzel-Gryglewska
et al. 2015). It is notable that ascending projections from the VTA have been
suggested to be critical for the generation of dreams (Solms 2000).
The effects of systemic administration of DAergic agents on sleep and W have

been reviewed by Monti and Monti (2007) and Monti and Jantos (2008). Briefly,
systemic administration of a selective D1 receptor agonist induces W together with
a reduction of NREM and REM sleep. Systemic injection of a D2 receptor agonist
induces biphasic effects, such that low doses reduce W and increase NREM and
REMS (predominant activation of the D2 autoreceptor), whereas larger doses
induce the opposite effect (i.e., W, by facilitation of the D2 postsynaptic receptor).
Compounds with D1 or D2 receptor blocking properties augment NREM sleep and
reduce W.
Wisor et al. (2001) quantified sleep and W in DAT knockout (KO) mice. These
animals showed a significant increase of W and a reduction of NREM sleep during
the light phase compared with wild-type littermates, probably related with an
increase in DA in the synaptic cleft.
3 The Melanin-Concentrating Hormone (MCH)
MCH is a neuropeptide originally described as a circulating hormone isolated from

salmon pituitaries (Kawauchi et al. 1983). MCH was subsequently identified as a
neuromodulator in mammals, including humans (reviewed by Bittencourt and Celis
2008; Saito and Nagasaki 2008; Bittencourt 2011; Macneil 2013). MCH is a cyclic
neuropeptide with 19 aminoacids that derives from the cleavage of a larger pre-
cursor of 165 aminoacids called prepro-MCH (ppMCH), from which it originates
two additional peptides: the neuropeptide EI (NEI) and neuropeptide GE (NGE). In
addition, the precursor has the potential to give rise to an alternative splice variant
termed MCH-gene-overprinted-polypeptide (MGOP) and also a portion of the
antisense-RNA-overlapping-MCH (AROM) (Toumaniantz et al. 1996; Borsu et al.
2000).
In many species, including rats, mice, cats, non-human primates and humans,
MCH is synthesized in neurons whose somata are located in the lateral sector of the
posterior hypothalamus, dorsomedial hypothalamus and incerto-hypothalamic area
(Torterolo et al. 2006; Bittencourt 2011). Important for the purpose of this chapter,
the incerto-hypothalamic area harbors not only MCH-containing neurons, but also
the A-13 DAergic neuronal group. However, MCH and DA do not co-localize (Sita
et al. 2003).
A small number of MCHergic neurons have been also identified in the olfactory
tubercle and the pontine reticular formation (Bittencourt et al. 1992). Intriguingly, it
seems that part of the MCH expression has sexual dimorphism, and MCH
expression depends on female reproductive state. In this regard, MCHergic neurons
are present in the medial preoptic area of lactating rats and in the LDT of female rats
(Rondini et al. 2007, 2010). MCH is also present in the gastrointestinal tract and
pancreas (Pissios et al. 2007; Kokkotou et al. 2008).
Two MCH receptors have been described (reviewed by Saito and Nagasaki
2008; Macneil 2013). The first MCH receptor discovered was the MCH receptor
type-1 (MCHR1). It constituted an orphan G-protein coupled receptor originally

named SLC-1. Thereafter, the MCH receptor type-2 (MCHR2) was found also as a
G-protein coupled receptor, and compared to MCHR1, have 38 % of homology in
its sequence. While MCHR1 is shared by all mammals studied up to date, MCHR2
is not functional in rodents. Receptor activation from binding of MCHR1 results on
diverse signaling pathways by coupling to Gi, Gq, and Go proteins and by inhi-
bition of Ca2+ currents, while MCHR2 is coupled to Gq protein (Hawes et al. 2000;
Sailer et al. 2001; Gao 2009; Macneil 2013). MCH has mainly an inhibitory role,
both at the presynaptic level, where it decreases the release of GABA and gluta-
mate, and at the postsynaptic site (Gao 2009; Macneil 2013).
The MCHergic system was traditionally related to the control of energy
homeostasis, i.e., feeding and metabolic activity (reviewed by Macneil 2013). In
this regard, chronic infusion of a synthetic MCHR1 agonist induces obesity in mice,
which is accompanied by hyperphagia, a reduction in body temperature and
stimulation of lipogenic activity in the liver as well as white adipose tissue.
Furthermore, genetically-modified animals with over-expression of MCH are obese,
whereas animals lacking MCH are hypophagic and lean. These data suggest that by
increasing food intake and promoting anabolism, MCH promotes the conservation
of body energy.
4 The MCHergic System Promotes Sleep
Conservation of energy is one of the main functions of sleep (Siegel 2005). Since
MCHergic neurons are critical in the control of energy homeostasis, they should be
involved in sleep regulation. MCH, via regulation of the activating and somnogenic
systems, promotes sleep, especially REM sleep (reviewed by Peyron et al. 2009;
Torterolo et al. 2011; Monti et al. 2013; Konadhode et al. 2015; Torterolo et al.
2015).
MCHergic neurons send dense projections to activating and somnogenic
regions. Using retrograde tracers, we have characterized the MCHergic neuronal
projections to the nucleus pontis oralis, the executive area for REM sleep generation
(Torterolo et al. 2009). There is also a high density of MCHergic fibers in activating
regions such as the tuberomammillary nucleus of the hypothalamus, BF, LDT and
PPT, DR and LC (Bittencourt et al. 1992; Torterolo et al. 2008; Lagos et al. 2011b;
Yoon and Lee 2013). Regions of the limbic system involved in the control of
emotional states including amygdala, NAc, septum and hippocampus also receive
MCHergic fibers and express MCH receptors (Bittencourt et al. 1992; Hervieu et al.
2000; Chee et al. 2013). A wide distribution of MCHR1 has been also identified in
the CNS of the rat, which coincides with the distribution of MCHergic fibers
(Lembo et al. 1999; Saito et al. 2001; Spaethling et al. 2014; Devera et al. 2015).
Using the Fos protein as a marker of neuronal activity, Verret et al. (2003)
showed that MCHergic neurons are active during the REM sleep rebound that
followed 72 h of REM sleep deprivation in male rats. Thereafter, they showed that
some of these active neurons corresponded to subpopulations of neurons that

co-express the cocaine and amphetamine regulated transcript (CART) (Hanriot
et al. 2007).
Furthermore, Hassani et al. (2009) recorded MCHergic neurons in non-
anesthetized animals. These neurons have a very low frequency of discharge during
W; their firing rate increases slightly during NREM sleep and reaches the maximum
level of activation during REM sleep. However, even during this state the average
discharge rate is still low (approximately 1 Hz) as compared with other neuronal
groups.
The concentration of MCH in the cerebro-spinal fluid (CSF) of rats increases
during the light phase, when the animals are predominantly asleep, while it
decreases during the dark period when rats are mainly awake (Pelluru et al. 2013).
Dias et al. (2015) also showed that the time of the day as well as sleep disruption
affect the MCH CSF levels as well as the expression of the ppMCH and MCHR1
genes. Utilizing the in vivo microdialysis technique, it has been shown that the
release of MCH in the amygdala of patients with treatment-resistant epilepsy is
minimal during active W induced by social interactions, increases after eating
(consummatory behavior), and reaches a maximum level at sleep onset (Blouin
et al. 2013).
Studies of ppMCH and MCHR1 KO mice indicate that the sleep architecture of
these animals is altered. Mice lacking MCH sleep less than wild-type animals
(Willie et al. 2008). Moreover, in response to fasting, MCH deficient mice became
hyperactive and show a marked decrease in REM sleep. Ahnaou et al. (2011)
described an increase of W and a reduction of NREM sleep in MCHR1 KO mice.
Moreover, restraint stress in these mutant mice further increases W and reduces
both NREM and REM sleep (Ahnaou et al. 2011).
Intracerebroventricular administration of MCH in the rat produces a marked
increase in REM sleep and a moderate enhancement in the time spent in NREM
sleep (Verret et al. 2003). Furthermore, the systemic administration of MCHR1
antagonists decrease both REM and NREM sleep and increase W (Ahnaou et al.
2008).
Microinjection of MCH into the DR of the rat facilitates the generation of REM
sleep (Lagos et al. 2009). Conversely, the immunoneutralization of endogenous
MCH within the DR (through the microinjection of anti-MCH antibodies) produces
the opposite effect (Lagos et al. 2011a). MCH also promotes REM sleep when
microinjected into either the BF of the rat or the NPO of the cat, two areas involved
in the generation of this behavioral state (Torterolo et al. 2009; Lagos et al. 2012).
Microinjections of MCH into the LC also produce a marked increase in REM sleep
(Monti et al. 2015). In contrast, the administration of MCH into the ventro-lateral
preoptic area (VLPO), a NREM sleep promoting region, induces NREM sleep
(Benedetto et al. 2013).
Optogenetic studies have confirmed the role of MCH in sleep generation (Jego
et al. 2013; Konadhode et al. 2013; Tsunematsu et al. 2014). Konadhode et al.
(2013) inserted the gene for the photosensitive rhodopsine-2-cation channel in
MCHergic neurons of mice, and specifically stimulated MCHergic neurons. The
stimulation of the MCHergic neurons induced a decrease in the latency to sleep

onset, reduced the duration of W and increased the total time spent in NREM and
REM sleep during the night, whereas it increased the depth of sleep during the day.
The authors hypothesized that MCHergic neurons are able to counteract the actions
of the activating systems. Consequently, it was concluded that MCHergic agonists
might be useful for the treatment of insomnia. Jego et al. (2013) found that acute
activation of MCH neurons at the onset of REM sleep extended the duration of
REM sleep episodes. In contrast, the inhibition of the MCHergic neurons reduced
the frequency and amplitude of the hippocampal theta rhythm during REM sleep
without affecting the duration of the episodes. Tsunematsu et al. (2014) showed that
acute optogenetic activation of MCH neurons at 10 Hz induced transitions from
NREM to REM sleep and increased REM sleep time. Acute optogenetic silencing
of MCHergic neurons had no effect on any vigilance state. On the contrary,
temporally-controlled ablation of MCH neurons by cell-specific expression of
diphtheria toxin A increased W and decreased NREM sleep duration without
affecting REM sleep (Jego et al. 2013; Konadhode et al. 2013; Tsunematsu et al.
2014). The authors concluded that acute activation of MCHergic neurons is suffi-
cient, but not necessary, to trigger the transition from NREM to REM sleep and that
MCHergic neurons also play a role in the initiation and maintenance of NREM
sleep.
Studies in vivo by Devera et al. (2015) have shown that MCH decreases the
firing rate of DR neurons, a component of the activating system. In agreement with
this electrophysiological result, in vivo microdialysis studies have shown that the
perfusion of low concentrations (30 lM) of MCH into the DR elicited a significant
decrease in extracellular serotonin levels within this region (Urbanavicius et al.
2016).
5 Interaction Between Dopaminergic and MCHergic

Systems in the Control of Behavioral States
The data reviewed tend to indicate that DAergic and MCHergic systems have
opposite functions. Accordingly, while the DAergic system promotes motivational
arousal, the MCHergic system promotes consummatory behavior and
sleep. However, regarding REM sleep, the data suggest a more complex scenario.
In this sense, MCH induces REM sleep, and it is likely that the DAergic neurons
promote at least some aspect of this state such as hippocampal theta rhythm and/or
dreams. Although the available indirect data strongly suggest an interaction
between both systems in the regulation of W and sleep, there are not direct studies
aimed to test this hypothesis.
5.1 Evidences from Genetically Modified Animals
MCHR1-KO mice present hyperactivity that may be explained by interactions

between MCHergic and DAergic systems (Marsh et al. 2002; Lalonde and Qian
2007). In fact, MCHR1-KO mice are super-sensitive to the locomotor activating
effects of d-amphetamine and D1 agonists as compared to wild-type animals.
Besides, deletion of MCHR1 results in an up-regulation of mesolimbic DA
receptors, and the lack of MCH leads to an increase in DA release and increased
limbic DA transporter levels, indicating that MCH may negatively modulate
mesolimbic monoamine function (Smith et al. 2005; Mul et al. 2011).
5.2 Effects of MCH on Dopaminergic Neurons
MCHergic neurons project towards the VTA (Bittencourt et al. 1992).

Notwithstanding this, Korotkova et al. (2003) have shown, by means of single-unit
extracellular and whole-cell patch-clamp recordings on DAergic neurons of the
VTA, that the application of MCH has no effect on the spike firing. The effects of
MCH on the SNc and vPAG have not been tested yet.
5.3 Interactions Between MCH and DA in the Nucleus

Accumbens
The NAc is a main target of the mesolimbic DAergic neurons, and has been
proposed as the neural interface between the limbic and motor system (Mogenson
et al. 1980). The NAc plays a critical role in reward-seeking behavior for natural
rewards and drugs of abuse (Castro et al. 2015; Volkow and Morales 2015). This
nucleus is one of the main projections sites of the MCHergic neurons and has an
important MCHR1 density (Bittencourt et al. 1992; Hervieu et al. 2000).
In an attempt to elucidate the role of DA and MCH in the control of motivation,
several studies have focused their attention in the interactions between them.
MCHR1 is co-expressed with DAergic receptors in the shell of the NAc, which
raises the possibility that MCH and DA interact in NAc shell during motivated
responses, such as food or drug seeking behavior (Georgescu et al. 2005; Chung
et al. 2009). In a whole-cell patch-clamp recording from the NAc shell, adminis-
tration of MCH alone had no effect on spike firing, but the discharge rate showed an
increase when MCH was applied in combination with D1 or D2 agonists (Chung
et al. 2009; Hopf et al. 2013). Furthermore, biochemical analysis in NAc shell
explants showed that MCH signaling blocks DA-induced phosphorylation of the
AMPA glutamate receptor (Georgescu et al. 2005).
6 Dopamine Regulates MCHergic Neurons
DA hyperpolarizes MCHergic neurons by activating G-protein-activated inwardly

rectifying K+ (GIRK) channels by means of the activation of alpha-2a noradren-
ergic receptors (Alberto et al. 2011; Conductier et al. 2011). Conductier et al.
(2011) also showed that MCH neurons receive more GABAergic inputs than
glutamatergic ones. In addition, they demonstrated that DA modulates these inputs
in a complex manner; at low concentrations DA activates D1-like receptors pro-
moting presynaptic activity. At higher concentrations DA activates D2-like receptor
that inhibits presynaptic activity. Overall, DA leads to a decrease in the excitability
of MCHergic neurons.
In contrast, local administration of DA agonist D1 or D2 in the lateral
hypothalamus or zona incerta revealed no effect on ppMCH gene expression
(Chen et al. 2014).
7 Lessons from Pathologies
7.1 Parkinson Disease
In addition to the degeneration of DAergic neurons, Parkinson’s disease (PD) is

accompanied by a decrease in the number of both hypocretinergic and MCHergic
neurons (Thannickal et al. 2007). The tentative relationship between a loss of
MCHergic activity and some symptoms of PD has not been studied yet; however, a
decrease in the activity of MCHergic cells could partly explain the high incidence
of the REM sleep behavior disorder in this pathology (Thorpy and Adler 2005).
New studies are needed in order to know the functional relationship between DA
and MCH in the physiopathology of PD.
In contrast, in Huntington’s disease there is a decrease in the number of
hypocretinergic neurons while the number of MCHergic neurons remains intact
(Aziz et al. 2008).
7.2 Major Depressive Disorder
The loss of pleasure in previously rewarding stimuli is called anhedonia, and is a

main symptom of depression. This feature may reflect an underlying defect in the
regulation of the reward processing. Due to the fact that the mesolimbic
dopaminergic system is critical in processing the rewarding salience of stimuli and
guiding action toward it, it is believed that DAergic system plays an important role
in depression (Heshmati and Russo 2015). In fact, anhedonia and depression are
common finding in PD, a pathology that courses with degeneration of the DAergic
neurons (Assogna et al. 2011). Furthermore, the facilitation of DAergic neuro-

transmission induced by chronic antidepressant treatments might contribute to their
therapeutic effects (D’Aquila et al. 2000).
There is a tight link between REM sleep and depression, where different features
of REM sleep are promoted in depressive patients (Palagini et al. 2013). MCH
promotes REM sleep and the up-regulation of the MCHergic system has been
proposed as one of the mechanism for depression (reviewed by Torterolo et al.
2015). In this respect, Schmidt et al. (2015) have shown that MCH serum levels
decrease following 4 weeks of antidepressant treatment in depressive patients.
Preclinical studies have demonstrated that MCHR1 antagonists have an enor-
mous potential as antidepressant drugs (Shimazaki et al. 2006; Chung et al. 2010).
Some of their beneficial effects can be attributed to MCH action on the DAergic
system. In this sense, chronic but not acute administration of SNAP 94847, a
MCHR1 antagonist, enhances locomotor activity induced by D2/D3 dopamine
agonists, which is a common effect induced by efficient antidepressants (Marsteller
et al. 2009).
7.3 Postpartum Emotional Distress
The medial preoptic area together with its interaction with components of the
mesolimbic dopamine system plays a critical role in motivational processes of
active maternal behavior (Stack et al. 2002; Miller and Lonstein 2005; Numan and
Stolzenberg 2009). It is notable that neurons of the medial preoptic area expressed
MCH only during the post-partum period (Rondini et al. 2010). Recently,
Benedetto et al. (2014) have shown that microinjections of MCH into this preoptic
area decrease active maternal behaviors. Hence, it would be important to know
whether a dysfunction of these MCH-containing neurons, or the interaction between
DA and MCH is related to emotional imbalances that take place in 75–80 % of
human mothers between 3 to 5 days after delivery (Lee 1998).
7.4 Narcolepsy
A DAergic dysfunction such as elevated D2 receptor binding in the striatum has

been described in human narcolepsy (Eisensehr et al. 2003). On the contrary,
MCHergic deficiencies have not been found in this pathology yet; while the number
of hypocretin-containing neurons degenerate in narcolepsy with cataplexy, the
MCHergic neurons that are intermingled with the former in the lateral hypothala-
mus do not (Thannickal et al. 2000). In addition, MCH levels in cerebrospinal fluid
are not modified in narcolepsy with cataplexy patients (Peyron et al. 2011).
7.5 Obesity
Obesity, which has reached an epidemic proportion, is related to non-homeostatic

mechanisms underlying the over-consumption of food. Because the DAergic
mesocorticolimbic system is a key substrate for non-homeostatic feeding, it may
play a critical role in obesity, and it is closely associated with food addiction (Baik
2013; Naef et al. 2015).
Preclinical studies have demonstrated that MCH is related to energy homeostasis
as a potent orexinergic lateral hypothalamic peptide. Furthermore, it has been
suggested that a dysfunction of the MCHergic system could lead to obesity
(Macneil 2013). In fact, mice over-expressing the ppMCH gene show increased
body weight and administration of MCH increased consumption of caloric rather
than non-caloric food, while chronic loss of MCH reduced meal size (Ludwig et al.
2001; Mul et al. 2011). It has been suggested that MCH would not be crucial to
initiate food consumption, but rather to amplify an already ongoing feeding
behavior and that antagonists accelerate satiety mechanisms (Nair et al. 2009; Mul
et al. 2011; Barson et al. 2013). There is one study that reports a trend toward an
association of several MCHR1 single-nucleotide polymorphisms with an obese
phenotype in groups of obese German children and adolescents (Wermter et al.
2005). Furthermore, MCHR1 antagonists are thought to be a therapeutic option for
treating obesity (Rivera et al. 2008).
Thus, MCH and DA seem to have complementary roles in feeding behavior and
hence in obesity, as proposed for other motivational behaviors. Although interac-
tions between DAergic and MCHergic system in food regulation have been pro-
posed (Gutierrez et al. 2011), the role of this interaction in over-consumption of
food is still unknown.
8 Conclusions and Future Directions
MCH promotes sleep. In order to do that, several evidences suggest that one
plausible mechanism is that MCHergic systems tend to reduce DAergic activity
involved in arousal. In addition, the arousal-promoting DAergic system tends to
inhibit MCHergic neurons.
Both MCHergic and mesolimbic DAergic systems are active during REM sleep;
regretfully, there are no studies focused to search for a probable functional inter-
action between both systems during this behavioral state.
There is evidence suggesting a functional link between the MCHergic and
DAergic systems in the pathophysiology of several medical conditions including
Parkinson disease and depression. More research is needed in order to clarify this
issue.
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Modulations of Ventral Tegmental Area
(VTA) Dopaminergic Neurons
by Hypocretins/Orexins: Implications
in Vigilance and Behavioral Control
Seiji Nishino and Noriaki Sakai
Abstract In this review, our current understandings of interactions of the

hypothalamic hypocretin/orexin (hcrt/ox) and midbrain VTA dopaminergic
(DAergic) systems will be discussed. We will first overview the (1) neurobiology of
wakefulness and (2) symptoms of narcolepsy, followed by discoveries of the
hcrt/ox system and hcrt/ox deficiency in narcolepsy. We will then discuss the
functional links between the VTA DAergic and hcrt/ox systems, by introducing the
results of anatomical and functional (electrophysiological /pharmacological results)
studies. Many neuroscientists are also interested in functional roles of the VTA
DAergic and hcrt/ox systems in reward-motivational behavior, food intake, and
nociception, and some of these results will also be briefly introduced.
1 Introduction
In this review, our current understandings of interactions of the hypothalamic

hypocretin/orexin (hcrt/ox) and midbrain ventral tegmental area (VTA) dopaminergic
(DAergic) systems will be discussed. While dopamine (DA) is a classical neuro-
transmitter known to be involved in vigilance, motor control and reward-motivational
behavior for many years, the discovery of the hcrt/ox system was only made recently
in 1998 by two independent research groups (De Lecea et al. 1998; Sakurai et al.
1998). One group called the peptides “hypocretin” because of their primary
hypothalamic localization and similarities with the hormone “secretin” (De Lecea
et al. 1998). The other group called the molecules “orexin” after observing that central
administration of these peptides increased appetite in rats (Sakurai et al. 1998). This
discovery of hcrt/ox was immediately followed by discoveries of narcolepsy genes
(i.e., hcrt/ox receptor (Lin et al. 1999) and peptide (Chemelli et al. 1999) genes) in
S. Nishino (&) N. Sakai

Sleep and Circadian Neurobiology Laboratory,
Stanford University School of Medicine, 3155 Porter Drive, Rm 2106,
Palo Alto, CA 94304, USA
e-mail: nishino@stanford.edu

DOI 10.1007/978-3-319-46437-4_5
66 S. Nishino and N. Sakai
animals in 1999, and the subsequent discovery, in 2000, of hcrt/ox ligand deficiency
in idiopathic cases of human narcolepsy-cataplexy (Nishino et al. 2000).
Narcolepsy is a prototypical central hypersomnia characterized by excessive day-
time sleepiness (EDS) and dissociated manifestations of rapid eye movement
(REM) sleep, such as cataplexy, hypnagogic or hypnopompic hallucinations, sleep
paralysis, automatic behavior (Nishino and Mignot 1997). Therefore, sleep researchers
immediately jumped into studying the roles of hcrt/ox in sleep/wake and REM sleep
regulations under both normal and pathological conditions (see Nishino 2011).
Although this article will mostly discuss the anatomical and functional inter-
actions between the hcrt/ox system and midbrain DAergic systems, it may be
difficult to specifically dissect these interactions since a series of anatomical and
functional studies demonstrated that the hcrt/ox system integrates and coordinates
multiple wake-promoting systems (such as monoamine and acetylcholine systems)
to keep subjects fully alert (Nishino et al. 2004; Espana and Scammell 2004). These
classical neurotransmitter systems are also involved as REM-on (a subset of
acetylcholine) and REM-off (most monoamine) neurons that regulate REM sleep
(Nishino et al. 2004; Espana and Scammell 2004).
In this review, we will thus first overview the (De Lecea et al. 1998) neurobi-
ology of wakefulness and (Sakurai et al. 1998) symptoms of narcolepsy, followed
by discoveries of the hcrt/ox system and hcrt/ox deficiency in narcolepsy.
We will then discuss the functional links between the VTA DAergic and hcrt/ox
systems by introducing the results of anatomical and functional (electrophysiological/
pharmacological results) studies.
Many neuroscientists are also interested in functional roles of the VTA DAergic
and hcrt/ox systems in reward-motivational behavior, food intake, and nociception,
and some of these results will also be briefly introduced.
2 Neurobiology of Wakefulness and the DA System
In order to help with the understanding of the hcrt/ox and DAergic interactions in
vigilance control, current understandings of neurobiology of wakefulness will first
be discussed. Sleep/wake is a complex physiology regulated by brain activity, and
multiple neurotransmitter systems such as monoamines, acetylcholine, excitatory
and inhibitory amino acids, peptides, purines, and neuronal and non-neuronal
humoral modulators (i.e., cytokines and prostaglandins) (Jones 2005) are likely to
be involved. Monoamines are perhaps the first neurotransmitters recognized to be
involved in wakefulness (Jouvet 1972), and the monoaminergic systems have been
the most common pharmacological targets for wake-promoting compounds in the
past years. On the other hand, most hypnotics target the gamma-aminobutyric acid
(GABA) ergic system, a main inhibitory neurotransmitter system in the brain
(Nishino et al. 2004).
Cholinergic neurons also play critical roles in cortical activation during wake-
fulness and during REM sleep (Jones 2005). Brainstem cholinergic neurons
Modulations of Ventral Tegmental Area (VTA) … 67
originating from the laterodorsal and pedunculopontine tegmental nuclei activate

thalamocortical signaling, and cortex activation is further reinforced by direct
cholinergic projections from the basal forebrain. However, currently no cholinergic
compounds are used in sleep medicine, perhaps due to the complex nature of the
systems and prominent peripheral side effects.
Monoamine neurons, such as norepinephrine (NE) containing locus coeruleus
(LC) neurons, serotonin (5-HT) containing raphe neurons, and histamine containing
tuberomammilary neurons (TMN) are wake-active and act directly on cortical and
subcortical regions to promote wakefulness (Jones 2005). In contrast to the focus on
these wake-active monoaminergic systems, researchers have often underestimated the
importance of DA in promoting wakefulness. Most likely, this is because the firing
rates of midbrain DA-producing neurons (VTA and substantia nigra [SN]) do not have
an obvious variation according to behavioral states (Steinfels et al. 1983). In addition,
DA is produced by many different cell groups (Björklund and Lindvall 1984), and
which of these promote wakefulness remains undetermined. Nevertheless, DA release
is greatest during wakefulness (Trulson 1985), and DA neurons increase discharge and
tend to fire bursts of action potentials in association with significant sensory stimu-
lation, purposive movement, or behavioral arousal (Ljungberg et al. 1992). Lesions
that include the DAergic neurons of the VTA reduce behavioral arousal (Jones et al.
1973). Recent work has also identified a small wake-active population of
DA-producing neurons in the ventral periaqueductal grey that project to other arousal
regions (Lu et al. 2006). People with DA deficiency from Parkinson’s disease are often
sleepy (Moller et al. 2000), and DA antagonists (or small doses of DA autoreceptor
(D2/3) agonists) are frequently sedating. These physiologic and clinical findings
clearly demonstrate that DA also plays a role in wakefulness.
Wakefulness and various physiology associated with wakefulness are essential
for the survival of creatures and thus, is likely to be regulated by multiple systems,
each having a distinct role. Some arousal systems may have essential roles for
cortical activation, attention, cognition, or neuroplasticity during wakefulness while
others may only be active during specific times to promote particular aspects of
wakefulness. Some of the examples may be motivated-behavior wakefulness or
wakefulness in emergency states, in which the DAergic system is likely to be a
major player. Wakefulness may thus likely be maintained by many systems with
differential roles coordinating in line. Similarly, wake-promoting mechanism of
some drugs may be unexplainable by a single neurotransmitter system.
3 Narcolepsy, a Prototypical Hypersomnia Associated

with REM Sleep Abnormalities
Narcolepsy is a syndrome of unknown etiology [prevalence = 1 in 2000 (Hublin

et al. 1994; Mignot 1998)] characterized by EDS that is often profound. About
95 % of narcoleptic cases are sporadic, but it also occurs in familial forms.
Narcolepsy usually occurs in association with cataplexy (a sudden loss of tonus of
antigravity muscles during wakefulness typically triggered by emotional excita-

tions) and other symptoms and signs, which commonly include hypnagogic or
hypnopompic hallucinations, sleep paralysis, automatic behavior, and disrupted
nocturnal sleep (ICSD-2 2005). Symptoms most often begin during adolescence or
young adulthood. Although EDS is not specific for narcolepsy and is seen in other
primary and secondary EDS disorders (such as sleep apnea syndrome), cataplexy is
generally regarded as pathognomonic.
Notably, sleep and wake are highly fragmented in narcolepsy, and affected subjects
cannot maintain long bouts of either state. Normal sleep physiology is currently
understood as being dependent upon coordination between facilitating sleep centers
and inhibiting arousal centers in the brain, such that stable sleep and wake states are
maintained for specific durations (Nishino et al. 2004). An ascending arousal pathway,
running from the rostral pons and through the midbrain reticular formation, promotes
wakefulness (Nishino et al. 2004; Saper et al. 2005) (see Neurobiology of
Wakefulness, above). This arousal pathway may be composed of neurotransmitters
(acetylcholine, NE, DA, excitatory amino acids), produced by brainstem and
hypothalamic neurons (hcrt/ox and histamine), and is also linked to muscle tonus
control during sleep (Nishino et al. 2004; Saper et al. 2005). Whereas full alertness and
cortical activation require coordination of these arousal networks, effective sleep
requires suppression of arousal by the hypothalamus (Saper et al. 2005). Narcolepsy
patients may thus experience major neurological malfunction of this control system.
Narcoleptics exhibit a phenomenon termed short REM sleep latency or sleep
onset REM period (SOREMP), in which patients enter into REM sleep earlier than
normal upon falling asleep, within 15 min of sleep onset (Nishino and Mignot
1997). In some cases, NREM sleep is completely bypassed, and the transition to
REM sleep occurs instantly (Nishino and Mignot 1997).
Moreover, intrusion of REM sleep into wakefulness may explain occurrences of
cataplexy, sleep paralysis, and hypnogogic hallucinations. However, whereas
paralysis and hallucinations manifest in other sleep disorders such as sleep apnea
syndromes and disturbed sleep patterns in the normal population (Aldrich et al.
1997), cataplexy is pathognomonic for narcolepsy (Nishino and Mignot 1997). As
such, identifying cataplexy’s unique pathophysiological mechanism emerged as
potentially pivotal to understanding the overall pathology underlying narcolepsy.
4 Discovery of Hypocretin/Orexin Deficiency in Human

Narcolepsy
The significant roles, first, of hcrt/ox deficiency and, subsequently, of postnatal cell
death of hcrt/ox neurons as the major pathophysiological process underlying nar-
colepsy with cataplexy, emerged from a decade of investigation, employing both
animal and human models. In 1998, the simultaneous discovery by two independent
research groups of a novel hypothalamic peptide neurotransmitter (named
“hypocretin” and “orexin” by each) proved pivotal (De Lecea et al. 1998; Sakurai
(a)
(b)
(c)
b Fig. 1 a Structures of mature hypocretin-1 (orexin-A) and hypocretin-2 (orexin-B) peptides. b

Schematic representation of the hypocretin (orexin) system. c Projections of hypocretin neurons in
the rat brain and relative abundances of hypocretin receptor 1 and 2. a The topology of the two
intrachain disulfide bonds in orexin-A is indicated in the above sequence. Amino acid identities are
indicated by shaded areas. b The actions of hypocretins are mediated via two G protein-coupled
receptors named hypocretin receptor 1 (Hcrtr 1) and hypocretin receptor 2 (Hcrtr 2), also known
as orexin-1 (OX1R) and orexin-2 (OX2R) receptors, respectively. Hcrtr 1 is selective for
hypocretin-1, whereas Hcrtr 2 is nonselective for both hypocretin-1 and hypocretin-2. Hcrtr 1 is
coupled exclusively to the Gq subclass of heterotrimeric G proteins, whereas in vitro experiments
suggest that Hcrtr 2 couples with Gi/o, and/or Gq (adapted from Sakurai 2002).
c Hypocretin-containing neurons project to these previously identified monoaminergic and
cholinergic and cholinoceptive regions where hypocretin receptors are enriched. The relative
abundance of Hcrtr 1 vs. Hcrtr 2 in each brain structure was indicated in parenthesis (data from
Marcus et al. 2001). Impairments of hypocretin input may thus result in cholinergic and
monoaminergic imbalance and generation of narcoleptic symptoms. Most drugs currently used for
the treatment of narcolepsy enhance monoaminergic neurotransmission and adjust these
symptoms. VTA ventral tegmental area; SN substantia nigra; LC locus coeruleus; LDT laterodorsal
tegmental nucleus; PPT pedunculopontine tegmental nucleus; RF reticular formation; BF basal
forebrain; VLPO ventrolateral preoptic nucleus; LHA lateral hypothalamic area; TMN tubero-
mamillary nucleus; DR dorsal raphe; Ach acetylcholine; Glu glutamate; GABA
gamma-aminobutyric acid; HI histamine; DA dopamine; NA noradrenalin, 5-HT serotonin
et al. 1998) (Fig. 1). These neurotransmitters are produced exclusively by thou-
sands of neurons, which are localized in the lateral hypothalamus (LH) and project
broadly to specific cerebral regions and more densely to others (Peyron et al. 1998).
Within a year Stanford researchers used positional cloning of a naturally-occurring
familial canine narcolepsy model and identified an autosomal recessive mutation of
hypocretin receptor 2 (hcrtr 2) responsible for canine narcolepsy, characterized by
cataplexy, reduced sleep latency, and SOREMPs (Lin et al. 1999). This finding
coincided with the observation of the narcolepsy phenotype in hcrt/ox ligand deficient
mice (prepro-orexin gene knockout mice), characterized by cataplectic behavior and
sleep fragmentation (Chemelli et al. 1999). Together, these findings confirmed hcrt/ox
peptides as principal sleep-modulating neurotransmitters and prompted investigation
of the involvement of hcrt/ox system in human narcolepsy.
Although screening of patients with cataplexy failed to implicate hcrt/ox-related
gene mutation as a major cause of human narcolepsy, narcoleptic patients did
exhibit low cerebrospinal fluid (CSF) levels of hypocretin-1 (Nishino et al. 2000).
Post-mortem brain tissue of narcoleptic patients, assessed through immunochem-
istry, radioimmunological peptide assays, and in situ hybridization, revealed hcrt/ox
peptides loss and undetectable levels of hcrt/ox peptides or pre-hcrt/ox RNA.
Furthermore, melanin-concentrating hormone neurons, also expressed at the same
brain region (Peyron et al. 2000), were observed intact, indicating that damage to
hcrt/ox neurons and production is selective in narcolepsy rather than due to gen-
eralized neuronal degeneration.
Soon after the discovery of human hcrt/ox deficiency, researchers identified
specific substances and genes, such as dynorphin and neuronal activity-regulated
pentraxin (NARP) (Crocker et al. 2005) and most recently, insulin-like growth
factor binding protein 3 (IGF BP3) (Honda et al. 2009), which colocalize in neurons
containing hcrt/ox. These findings underscored selective hcrt/ox cell death as the
cause of hcrt/ox deficiency (as opposed to transcription/biosynthesis or hcrt/ox
peptide processing problems) because these substances are also deficient in the
postmortem brain lateral hypothalamic area of hcrt/ox deficient narcoleptic patients
(Crocker et al. 2005; Honda et al. 2009). Further, in view of the generally late
onsets of sporadic narcolepsy compared with those of familial cases, these studies
suggest that postnatal cell death of hcrt/ox neurons constitutes the major patho-
physiological process in human narcolepsy with cataplexy.
Narcolepsy is associated with the human leukocyte antigen (HLA)-DQB1*0602
allele (Mignot et al. 1997). Many have therefore hypothesized that narcolepsy is
caused by an autoimmune process that kills the hcrt/ox-producing neurons. This
perspective was further reinforced recently by the observation that narcolepsy is
also associated with a polymorphism in the T-cell receptor alpha gene (Hallmayer
et al. 2009), but still, direct evidence for an autoimmune process has been lacking.
5 Hypocretin/Orexin Peptides and Their Receptors
Hypocretins/orexins (hypocretin-1 and hypocretin-2/Orexin A and Orexin B) are

cleaved from a precursor preprohypocretin (prepro-orexin) peptide (De Lecea et al.
1998; Sakurai et al. 1998; Sakurai 2002). Hypocretin-1 with 33 residues contains
four cysteine residues forming two disulfide bonds. Hypocretin-2 consists of 28
amino acids and shares similar sequence homology, especially at the C-terminal
side, but has no disulfide bonds and is a linear peptide (Sakurai et al. 1998) (Fig. 1).
There are two G-protein-coupled hcrt/ox receptors—hcrtr 1 and hcrtr 2, also called
orexin receptor 1 and 2 (Ox1R and Ox2R). A distinct distribution of these receptors
in the brain is known: hcrtr 1 is enriched in the ventromedial hypothalamic nucleus,
tenia tecta, the hippocampal formation, dorsal raphe, and LC. In contrast, hcrtr 2 is
enriched in the hypothalamic paraventricular nucleus, cerebral cortex, NAc, VTA,
SN, and histaminergic TMN (Marcus et al. 2001, Trivedi et al. 1998; Lu et al.
1999). Hcrt-1 (OxA) and hcrt-2 (OxB) are produced exclusively by a well-defined
group of neurons localized in the LH. The neurons project to the olfactory bulb,
cerebral cortex, thalamus, hypothalamus, and brainstem, particularly the LC, VTA,
raphe nucleus, as well as to the cholinergic nuclei (the laterodorsal tegmental and
pedunculopontine tegmental nuclei) and cholinoceptive sites (such as pontine
reticular formation), which are thought to be important for sleep regulation (Peyron
et al. 1998; Sakurai 2002).
A series of recent studies have now shown that the hcrt/ox system is a major
excitatory system, which affects the activity of monoaminergic (DA, NE, 5-HT and
histamine) and cholinergic systems, significantly affecting vigilance states (Sakurai
2002; Willie et al. 2001). Thus, it is likely that a deficiency in hcrt/ox neuro-
transmission induces an imbalance between these classic neurotransmitter systems,
with primary effects on sleep-state organization and vigilance.
Hcrt/ox levels increase during the active periods and are highest at the end of the
active period, with the levels declining at sleep onset. Furthermore, sleep depri-
vation increases hcrt/ox levels (Fujiki et al. 2001; Yoshida et al. 2001).
Electrophysiological studies have shown that hcrt/ox neurons are active during
wakefulness and reduce the activity during slow wave sleep (Lee et al. 2005). The
neuronal activity during REM sleep is the lowest, but intermittent increases in the
activity, associated with body movements or phasic REM activity, are observed
(Lee et al. 2005).
6 Hypocretin/Orexin Deficiency and Narcoleptic

Phenotype
Human studies have demonstrated that the occurrence of cataplexy is closely

associated with hcrt/ox ligand deficiency (Mignot et al. 2002). Furthermore, the
hcrt/ox deficiency was already observed at the very early stages of the disease (just
after the onset of EDS), even before the occurrences of clear cataplexy.
Sleepiness in narcolepsy is most likely due to the patients’ difficulty in main-
taining wakefulness as normal subjects do. One of the most important character-
istics of EDS in narcolepsy is that sleepiness is reduced, and patients feel refreshed
after a short nap; however, this does not last long, and patients become sleepy
within a short period of time. The sleep pattern of narcoleptic subjects is also
fragmented; they exhibit insomnia (frequent wakening) at night. This fragmentation
occurs across 24 h, thus, the loss of hcrt/ox signaling likely plays a role in this
vigilance stage stability (see Saper et al. 2001), but other mechanism may also be
involved in EDS in narcoleptic subjects.
7 DA Involvements in Hypocretin/Orexin Deficient

Narcolepsy
The interaction of hcrt/ox and DA is only one of the many important regulatory
systems involved in vigilance control. However, there are many experimental
evidences that directly and indirectly suggest significances of hcrt/ox and DA
interactions in vigilance and behavioral control in health and disease. These find-
ings in human narcolepsy (mostly hcrt/ox ligand deficiency) and familial nar-
coleptic dogs (i.e., hcrtr 2 mutated) are summarized.
1. Pharmacological data
Over 90 % of diagnosed narcoleptic patients are reported to take medications to
control symptoms (Nishino and Kotorii 2010). Pharmacological treatments for EDS of
narcolepsy include amphetamine-like central nervous system (CNS) stimulants and
modafinil and its r-enantiomer. Other less commonly used stimulants are compounds
with DA uptake inhibitions. In almost all cases, the effects on vigilance were found to
be mediated via the effects on the DA transporter (DAT), although the mode of action
of modafinil remains controversial (Nishino 2010; Nishino and Mignot 2005). These
compounds do not improve cataplexy and other REM sleep abnormalities (hypno-
gogic hallucinations and sleep paralysis), so antidepressants (monoamine uptake
inhibitors) are additionally used for the treatment of cataplexy and REM sleep
abnormalities. Sodium oxybate, an approved formula of gamma hydroxybutyrate
(GHB) in the USA, given at night improves both EDS and cataplexy (Nishino 2010).
Although improvement in sleepiness occurs relatively quickly, anti-cataplectic effects
appeared 1–2 weeks after the initiation of the treatment. The modes of actions of
Sodium oxybate on EDS and cataplexy are mostly unknown. Central actions of
sodium oxybate may be mediated by direct actions on GHB and/or GABAB receptors
or through its metabolite, GABA (Nishino 2010). Sodium oxybate also affects DA
release, and the effects vary depending on the dose.
Experiments in canine narcolepsy suggest a preferential involvement of NE rather
than 5HT reuptake inhibition in the anti-cataplectic properties of the drugs. DA
reuptake inhibition does not reduce cataplexy, but does significantly enhance wake-
fulness (Nishino and Mignot 1997; Nishino et al. 1998). In humans, compounds with
NE reuptake inhibition also reduce cataplexy. Recently, selective NE and NE/5-HT
(SNRI) reuptake inhibitors were introduced, and one of the SNRIs, venlafaxine, has
become the first line anticataplectic medication (Nishino and Kotorii 2010).
Pharmacological evaluations for mechanisms triggering cataplexy were inten-
sively studied using narcoleptic Dobermans (i.e., hcrtr 2 mutation) (Nishino and
Mignot 1997). We generally consider that cataplexy-enhancing effects are more
specific than cataplexy reducing effects for drug administration, as many drugs
when used at high doses generally reduce cataplexy. In contrast, only few classes of
compounds aggravate cataplexy.
Narcoleptic dogs are very sensitive to alpha-1b blockade and alpha-2 stimulation
as well as DA D2/D3 stimulation and exhibit cataplexy (ICSD-2 2005). Also, they
are sensitive to cholinergic M2/3 stimulation and exhibit cataplexy, and upregu-
lation of muscarinic receptors in the pons was reported (see ICSD-2 2005). Among
them, the cataplexy-enhancing effects by DA D2/D3 stimulation, such as by
quinpirole and 7-OH-DOPAT, is drastic, and very low doses of drugs induce
cataplexy even in dogs that rarely have spontaneous cataplexy. The effects are not
associated with any noticeable side effects except for very short-lasting vomiting
(ICSD-2 2005). Local drug perfusion experiments using microdialysis revealed that
the sites of D2/D3 agonists include the VTA, SN, and A11 (Honda et al. 1999; Reid
et al. 1996; Okura et al. 2004). Effects by D2/D3 mediation were selective among
other DA receptors, and D2 antagonists such as raclopride reduce cataplexy, while a
D1 agonist (SKF-38393), a D1 antagonist (SCH-23390) and DA uptake inhibition
(bupropion) had no effects on cataplexy (see Fig. 2 for the results of the SN
perfusion). Of note, VTA perfusion of quinpirole significantly increased the drowsy
state, while the SN perfusion did not modify sleep (Honda et al. 1999).
Induction of cataplexy by DA D2/D3 stimulation was also reported recently in
a mouse model of narcolepsy (i.e., hcrt/ox KO mice) by Burgess et al. (2010).
1500
1400
(Percent change from baseline)

1300
1200
*
Time spent in cataplexy
D2(3) +
1100
1000
900
800
700
600
500
400
D2(3) -
300
200
100
* D1 + D1 - DA T -
0
Quinpirole 7-OH-DPAT Raclopride SKF-38393 SCH-23390 Bupropion
Dose (10-2 M)
Fig. 2 Effects on cataplexy of bilateral perfusion of various dopamine compounds into the SNr.
The bar graphs represent the percent change in time spent in cataplexy during each drug session, as
compared to their respective baseline levels. Cataplexy was tested using the FECT during each
perfusion period. The dose (104 ±102 M) of drugs was increased every 40 min after the 40 min
baseline session when arti®cial CSF was perfused. The highest dose of quinpirole (D2a3 agonist)
and 7-OH-DPAT (D3 selective agonist) significantly aggravated canine cataplexy. In contrast, the
D2/D3 antagonist raclopride significantly reduced cataplexy. Neither the D1 agonist (SKF-38393)
nor the D1 antagonist (SCH-23390) mediated canine cataplexy. The DA uptake inhibitor,
bupropion, had no effect on cataplexy
These results are however puzzling if we contrast this with the effects of DAT
uptake inhibitors on cataplexy: DAT uptake inhibitors significantly promote
wakefulness, but have no effects on cataplexy and little effects on REM sleep
(Nishino et al. 1998). Remarkably, results in narcoleptic dogs suggested that cata-
plexy was significantly reduced by D2/D3 antagonists whereas REM sleep was not
(Okura et al. 2000). The results may suggest that DA by D2/D3 receptor mechanisms
are more specifically involved in regulation of cataplexy than regulation of REM
sleep inductions. In other words, D2/D3 mechanisms may be more closely related to
emotional triggering of cataplexy, whereas NE mechanisms may be more closely
related to the executive system for muscle atonia during REM sleep and cataplexy.
Mechanisms for cataplexy and REM sleep abnormalities associated with
impaired hcrt/ox neurotransmission have also been studied by several authors
(Kantor et al. 2009). Hcrt/ox significantly inhibits REM sleep in vivo, but activates
both brainstem REM-off LC and raphe neurons, REM-on cholinergic neurons as
well as local GABAnergic neurons in vitro, and this fact is somewhat puzzling.
Koyama (personal communication) suggested that disfacilitation of REM-off
monoaminergic neurons and disinhibition of REM-on cholinergic neurons, medi-
ated through disfacilitation of inhibitory GABAnergic interneurons (associated with
impaired hcrt/ox neurotransmission), are responsible for the occurrence of abnormal
REM sleep manifestations.
There are anecdotal reports indicating that narcoleptic humans might be resistant
to amphetamine abuse. In four studies totaling 251 narcoleptic patients receiving
amphetamine-like stimulants, there were only two cases of amphetamine psychosis
(one with addiction), two cases of hallucination, and three cases of addiction
(Akimoto et al. 1960; Parkes et al. 1975; Guilleminault et al. 1974; Passouant and
Billiard 1976). It was also reported that the majority of narcoleptic subjects reduced
their prescribed dosage of stimulants or had not taken any of the stimulants (Rogers
et al. 1997). These reports suggest that hct/ox deficient narcolepsy is an important
model to study the basic mechanism of psychostimulant abuse.
2. Neurochemical Data
Studies in humans with narcolepsy have shown a decrease in DA concentration
in the CSF (Montplaisir et al. 1982). Studies on hcrtr 2 mutated narcoleptic dogs,
performed before and after probenecid administration, demonstrated an altered
monoamine turnover with significantly less free homovanillic acid (HVA), dihy-
droxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylglycol (MHPG),
and 5-hydroxyindoleacetic acid (5-HIAA) (Lu et al. 1999).
Analyses of both human and animal narcoleptic brain tissue also suggest
DAergic dysfunction. In postmortem human autoradiographic studies, striatal DA
D2 receptor binding was increased more than D1 receptors in narcolepsy (Aldrich
et al. 1992). However, most in vivo studies with single-photon emission computed
tomography (Hublin et al. 1994) and positron emission tomography (Rinne et al.
1995) found no increase in striatal D2 receptor binding in narcolepsy.
Three independent studies reported altered catecholamine contents in the brains of
narcoleptic dogs (Faull et al. 1986; Mefford et al. 1983). These studies found increases
in DA and NE in many brain structures, especially DA in the amygdala and NE in the
pontis reticularis oralis (Faull et al. 1986; Mefford et al. 1983). These changes are not
due to a reduction in the turnover of these monoamines in the brain, since the turnover
of these monoamines is either high or not altered (Nishino et al. 2001). Considering
that the drugs which enhance DAergic neurotransmission (such as amphetamine-like
stimulants and modafinil [for EDS]) and NE neurotransmission (such as noradrenaline
uptake blockers [for cataplexy]) are needed to treat the symptoms in these animals
(Nishino and Mignot 1997), increases in DA and NE contents in the brain may be
compensatory; however, these findings are not consistent with the CSF findings.
Most of these abnormalities are likely secondary to the deficiency in hcrt/ox
neurotransmission, but alterations in these systems may actively mediate some of
sleep related symptoms of narcolepsy.
8 Anatomical and Functional Correlates

of the Hypocretin/Orexin and Dopaminergic Systems
Uramura et al. (2001), Nakamura et al. (2000) is perhaps the first group to present
the results that hcrt/ox activates the VTA DA neurons and induces hyperlocomotion
and stereotyped behavior, by measuring phospholipase C- and protein kinase
C-mediated Ca2+ signaling of VTA DA neurons.
Since then, a series of anatomical, electrophysiological and pharmacological

results studying interaction of hcr/ox systems and VTA DA system has been
published, and these studies are reviewed in chronological order.
1. Anatomical data
Anatomical studies of brainstem DA systems have demonstrated two subdivisions
of ascending DA projections from the mesencephalic DA nuclei, VTA area and SN
(De Lecea et al. 1998). The mesostriatal system (nigrostriatal system in older classi-
fications) projects to all three important subdivisions: the caudate (CAu) nucleus, the
putamen, and the ventral striatum (which includes the nucleus accumbens NAc). More
precisely, this system originates in the SN and terminates in the dorsal striatum (e.g.,
CAu) and the putamen, and the VTA projects to the ventral striatum, the tuberculum
olfactorium, and the bed nucleus of the stria terminalis (Sakurai et al. 1998). The
mesolimbocortical system (mesolimbic system in older terminologies) originates in the
VTA and the medial SN and terminates in the septum, the amygdala, the piriform,
entorhinal, prefrontal and anterior cingulate cortices, and in the habenula and other
limbic systems (Bjorklund and Lindvall 1984; Oades and Halliday 1987). The
involvement of the DA system and the basal ganglia and the thalamo-cortical circuitry
for the control of motor function is well described (Alexander 1996; Cliax et al. 1996;
Wichmann and Delong 1996; Chesselet and Delfs 1996; Albin et al. 1989; Alexander
et al. 1990; Hoover and Strick 1993; Gerfen 1995). Although the basal ganglia consist
of four nuclei [the striatum, globus pallidus, SN, and subthalamic nucleus (STN)],
these do not have direct input or output connections with the spinal cord. Therefore,
motor areas of the frontal cortex largely mediate the motor functions of the basal
ganglia (Alexander 1996; Cliax et al. 1996; Wichmann and Delong 1996; Chesselet
and Delfs 1996; Albin et al. 1989; Alexander et al. 1990; Hoover and Strick 1993;
Gerfen 1995).
A series of experimental evidences had suggested that the mesolimbocortical
system is important for sleep/wake control (over the mesostriatal system). The
mesolimbocortical system may also be critically involved in the induction of cat-
aplexy, since we had demonstrated that local perfusion of D2/3 agonists in the VTA
(A10) and (A11) significantly aggravated cataplexy in narcoleptic Dobermans (Reid
et al. 1996; Okura et al. 2004).
As previously described, hcrt/ox neurons project densely to the VTA and SN
(Fig. 3) as well as to other monoaminergic nuclei, such as the TMN, LC, and raphe
(Peyron et al. 1998). However, subsequent anatomical studies reported that hcrt/ox
neurons exhibit relatively few synaptic contacts with VTA DA and VTA GABA
neurons and neurons that project to the prefrontal cortex (presumed DA neurons)
(Del Cid-Pellitero and Garzon 2014; Balcita-Pedicino and Sesack 2007).
Two independent anatomical studies provide ultrastructural evidence of only a
small proportion of hcrt/ox-positive axons with synaptic connections onto the
dendrites or soma of VTA DA neurons (as well as GABA neurons) (Fig. 4) (Del
Cid-Pellitero and Garzon 2014; Balcita-Pedicino and Sesack 2007). The synapses
included both asymmetric and symmetric types, and targeted TH- and
GABA-labeled profiles with equal frequency. These findings suggest that most
hcrt/ox fibers in the VTA are axons passing to caudal brainstem structures.
Fig. 3 Location of Fluorogold (FG) injections in the prelimbic region (PL) of the medial
prefrontal cortex and FG-labeled neurons in the ventral tegmental area (VTA). a Sagittal scheme
shows all FG infusions in PL (n = 10; modified from Swanson 1998). b Coronal section showing
an FG deposit in PL using immunohistochemistry in one animal. (c, d) Representative coronal
brainstem drawings showing FG-immunolabeled neurons (red dots) in the VTA of one of the PL
group rats. e Nissl-stained section adjacent to the section shown in F, which delineates the
subdivisions of VTA. f Panoramic photomicrograph showing FG-labeled neurons in the
parabrachial subdivision (PBP) of VTA. g High magnification of box “G” from F showing
FG-labeled neurons in the PBP of VTA ipsilateral to the FG injection site. The peroxidase
immunoreaction product can be clearly observed in the cytoplasm of cell bodies and proximal
dendritic branches (arrow). h High magnification of box h from F, showing much weaker
FG-retrograde labeling (arrow) in the PBP of VTA contralateral to the FG injection. ac anterior
commissure; Cg1 cingular cortex; CLi caudal linear raphe nucleus; DRN dorsal raphe nucleus; Fm
forceps minor of the corpus callosum; fr fasciculus retroflexus; IF interfascicular subdivision of
VTA; IP interpeduncular nucleus; M2 secondary frontal cortex; mlf medial longitudinal fasciculus;
MO medial orbital cortex; ob olfactory bulb; mp mammillary peduncle; PAG periaqueductal gray;
PN paranigral subdivision of VTA; ri rhinal incisure; RLi rostral linear raphe nucleus; RN red
nucleus; rs rhinal sulcus; SC superior colliculus; SNc substantia nigra pars compacta; SNr
substantia nigra pars reticulata. Scale bars, B, 1 mm, E-F, 500 lm, G-H, 100 lm. (from Del
Cid-Pellitero and Garzon 2014 with a permission)
b Fig. 4 Cellular contacts established by Hcrt1/OxA-containing axons in the ventral tegmental area.
a Hcrt1/OxA-immunoreactivity is seen in large dense-cored vesicles (ldcv), dense-cored vesicles
(dcv) and in the cytoplasm of a varicosity (Hcrt1/OxA-V) that makes an asymmetric synapse
(curved arrow) with a Fluorogold-labeled dendrite (FG-den). The FG-den is identified by its
content in DAB-immunoperoxidase reaction product (black arrows). b Hcrt1/OxA-V establishes
an asymmetric synapse (curved arrow) with a FG-dendrite that receives convergent input from an
unlabeled axon terminal (Ter). c A VTA dendrite (Den) receives a synaptic contact (curved arrow)
from an Hcrt1/OxA-immunoreactive varicosity (Hcrt1/OxA-V) and an unlabeled Ter.
d Hcrt1/OxA-T makes an asymmetric synapse (curved arrow) on an unlabeled Den.
Hcrt1/OxA-T contains translucent small synaptic vesicles (ssv) near the synaptic specialization
while dcv are far from the synapse. e Bar graph showing the relative percentage of appositional
and synaptic contacts (asymmetric) established by Hcrt1/OxA-boutons with unlabeled- (un) or
FG-labeled (FG) dendrites according to the type of axonal bouton (varicosity, diameter < 0.7 lm
or axon terminal, diameter 0.7 lm) in the ventral tegmental area. Mean percentages and
standard errors were calculated based on the numbers obtained from 102
Hcrt1/OxA-immunoreactive boutons in 14 vibratome sections from six rat brains. f Bar graph
showing the percentage distribution of unlabeled and Fluorogold-labeled (FG) dendrites of
different sizes receiving asymmetric synapses (n = 22) from Hcrt1/OxA-immunolabeled axonal
boutons (terminals and varicosities; total sample: 616 boutons) in the ventral tegmental area. Mean
percentages and standard errors were calculated based on the numbers obtained from the
synapse-recipient 22 dendrites in 18 ultrathin sections from 6 rat brains. ANOVA (animal X
dendritic size) was done to determine in those dendrites significant variations in the formation of
asymmetric synapses with respect to their small (< 0.5 mm), intermediate (0.5–1.0 mm) or large
(> 1.0 mm) diameters [*p < 0.05; post hoc Fisher test]. Scale bar, 0.2 lm (from Del Cid-Pellitero
and Garzon 2014 with a permission
However, hcrt/ox does mediate some direct synaptic influence on VTA DA and
GABA neurons. Additional nonsynaptic effects are suggested by the presence of
numerous dense-core vesicles. Hcrt/ox neurons exert a direct synaptic influence on
mesocortical neurons that would possibly facilitate arousal.
2. Electrophysiological and pharmacological results
Korotkova et al. (2003, 2006) reported with single-unit extracellular and
whole-cell patch-clamp recordings of VTA DA neurons that hcrt/ox caused various
effects on VTA DA neurons: an increase in firing frequency, burst firing, or no
change in firing in different groups of VTA DA neurons. Neurons showing oscil-
latory firing in response to hcrt/ox had smaller afterhyperpolarizations than the
other groups of DA neurons. Hcrt/ox also increased the firing frequency of
non-DAergic neurons in the VTA. In the presence of tetrodotoxin, hcrt/ox depo-
larized both DAergic and non-DAergic neurons, indicating a direct postsynaptic
effect. Single-cell PCR experiments also showed that hcrt/ox receptors were
expressed in both DAergic and non-DAnergic neurons (Fig. 5).
Along with these reports, Narita et al. (2006) also reported that the levels of DA
and its major metabolites in the NAc were markedly increased by the microinjection
of hcrt 1/ox A and hcrt 2/ox B into the VTA, suggesting that hcrt/ox stimulate DA
transmission of VTA DA neurons.
Vittoz and Berridge (2006) evaluated the effect of intracerebroventricular infu-
sion of hcrt-1 (0.07, 0.7 nmol) on extracellular levels of DA within the prefrontal
Fig. 5 Electrophysiological properties of dopaminergic neurons and their response to hcrt/ox.

a Double stainings of biocytin-filled neuron (red) and TH-immunoreactive neurons (green).
Arrows indicate the position of the neuron in the tissue. This biocytin-filled neuron is TH positive.
Scale bar, 50 m. b Voltage responses to current pulses (0.4, 0, 0.1 pA). c Chart recording of
membrane potential and spontaneous action potentials before and after application of hcrt/ox A
(100 nM). Hcrt/ox A was applied for 2 min. d Orexin B (100 nM) caused depolarization in the
presence of tetrodotoxin (0.5 M). e Example of a TH-positive neuron in which application of
orexin B (100 nM) caused burst firing. f A typical hcrt/ox-mediated burst from (Korotkova et al.
2003) with a permission
cortex (PFC) and NAc in the unanesthetized rat. Hcrt-1 dose-dependently increased
PFC dialysate DA levels (but not NAc DA levels), and these increases were closely
correlated with increases in time spent awake. The authors also confirmed that
unilateral infusion of hcrt-1 (0.1, 1.0 nmol) within the VTA increased PFC, but not
NAc dialysate DA levels.
The same authors (Vittoz et al. 2008) also reported that hcrt/ox significantly
increased Fos-immunoreactive (Fos-ir) in the VTA DA (tyrosine hydroxylase
immunoreactive [TH-ir]) neurons, primarily in a restricted population of
small-to-medium-sized DA neurons located within the caudomedial VTA.
Furthermore, within this region of the VTA, PFC- and NAs-projecting TH-ir
neurons were more likely to contain Fos-ir than were NAc-projecting TH-ir neu-
rons. These results provide novel evidence that hcrt/ox selectively activates PFC-
and NAs-projecting DA neurons within the VTA, and suggest a potential role for
hcrt/ox in PFC- and NAs-dependent cognitive and/or affective process.
It is also well known that antipsychotic drugs alter the activity of DA neurons in
the VTA and SN (A9). Rasmussen et al. (2007) reported that acute administration
of SB-334867 (an hcrtr 1/Ox1R antagonist) alone did not alter the number of
spontaneously active A9 or A10 cells, but did reverse the following: (1) the increase
in the number of spontaneously active A9 and/or A10 DA cells caused by the acute
administration of haloperidol (1 mg/kg, subcutaneous) (2) the decrease in the
number of spontaneously active A9 and/or A10 DA cells caused by the chronic
administration of haloperidol (1 mg/kg/day 21 days, s.c.). These results indicate
that activation of hcrtr 1/Ox1R receptors plays an important role on the effects of
antipsychotic drugs on DA neuronal activity and may play an important role in the
clinical effects of antipsychotic drugs.
DA neurons also project to the LH, and regulation of hcrt/ox neurons by DA has
also been studied. Li and van den Pol (2005), Yamanaka et al. (2006) reported that
NE, DA, and epinephrine directly hyperpolarized hcrt/ox neurons. NE neurons also
project to the LH and regulate the hcrt/ox neurons. These authors also reported an
indirect inhibition of hcrt/ox neurons by NE through increased inhibitory GABA
input, but whether there are similar mechanisms by DA (i.e., indirect inhibition of
hcrt/ox neurons by DA) was not evaluated.
Bubser et al. (2005) reported that a mixed DA agonist apomorphine increased
Fos expression in hcrt/ox cells, with a greater effect on hcrt/ox neurons located
medial to the fornix. Both the selective D1-like agonist A-77636 and the D2-like
agonist quinpirole also induced Fos in hcrt/ox cells, suggesting that stimulation of
either receptor subtype is sufficient to activate hcrt/ox neurons. Consistent with this
finding, combined SCH 23390 (D1 antagonist)-haloperidol (D2 antagonist) pre-
treatment blocked apomorphine-induced activation of medial as well as LH hcrt/ox
neurons. In situ hybridization histochemistry revealed that LH/PFC cells rarely
express mRNAs encoding DA receptors, suggesting that hcrt/ox cells are transsy-
naptically activated by apomorphine.
Alberto et al. (2006) monitored pharmacologically isolated action potential-
independent miniature excitatory postsynaptic current (EPSCs) [mEPSCs]. Bath
application of DA dose dependently induced a bidirectional effect on the excitatory
synaptic transmission. A low dose of DA (1 microM) increased mEPSC frequency,
which was blocked by the D1-like receptor antagonist SCH 23390, and mimicked
by the D1-like receptor agonist SKF 81297. In contrast, higher doses of DA (10–
100 microM) decreased mEPSC frequency, which could be blocked with the
D2-like receptor antagonist sulpiride. Quinpirole, a D2-like receptor agonist, also
reduced mEPSC frequency. None of these compounds affected the mEPSCs
amplitude, suggesting the locus of action was presynaptic. In addition, DA (1
microM) induced an increase in the action potential firing whereas DA (100
microM) hyperpolarized and ceased the firing of hcrt/ox neurons, indicating the
effect of DA on excitatory synaptic transmission may influence the activity of the
postsynaptic cell. These results suggest a reciprocal interaction between the hcr/ox
and VTA DAergic system, and these are also likely involved in conditioned
behavioral responses to reward-associated stimuli.
9 Hypocretin/Ox and Dopaminergic Systems in Other

Diseases/Physiology
As discussed above, several authors reported that hcrt/ox selectively activates PFC-
and NAs-projecting DA neurons within the VTA and suggest a potential role for
hcrt/ox in PFC- and NAs-dependent cognitive and/or affective processes via actions
on the mesolimbic DA system.
Taslimi et al. (2012) investigated the effect of direct administration of orexin A
into the VTA and examined the role of intra-NAc DA receptors in development
(acquisition) of reward-related behaviors in rats. The results showed that unilateral

intra-VTA administration of orexin A (27, 53 and 107 ng/0.3 ll saline) during the
conditioning phase induced conditional place preference (CPP) in a dose-dependent
manner. The most effective dose of intra-VTA orexin-A in eliciting CPP was
107 ng. However, intra-NAc administration of SCH 23390 (0.25, 1 and 4 lg/0.5 ll
saline), a D1 receptor antagonist, and sulpiride (0.25, 1 and 4 lg/0.5 ll DMSO), a
D2 receptor antagonist, inhibited the development of orexin-induced CPP.
These results taken together with the anecdotal findings that hcrt/ox deficient
narcolepsy may be resistant to stimulant abuse (see above) lead to many investi-
gators studying the roles of interactions of hcrt/ox and mesolimbic DA systems in
conditioned behavioral responses to reward-associated stimuli. These include
amphetamine, cocaine (Borgland et al. 2006; James et al. 2011), morphine (opioid)
(Narita et al. 2006; Baimel et al. 2015; Baimel and Borgland 2015).
With a mouse model of hcrt/ox deficient narcolepsy (i.e., orexin/ataxin 3
transgenic [TG] mice), we have also studied if they are resistant to establish
amphetamine-induced CPP (Sagawa et al. 2011). Indeed, both the TG narcoleptic
and wild type mice equally established CPP, but enhancement of CPP establish-
ment by applying stress, such as by food restriction, was attenuated in TG mice.
The results rather suggested changes in stress responses are involved in alternations
in CPP observed in hcrt/ox deficient narcolepsy (Sagawa et al. 2011).
Aston-Jones et al. (Moorman and Aston-Jones 2010; Aston-Jones et al. 2009)
reported that application of hcrt/ox onto VTA DA neurons increased baseline
activity and augmented or revealed excitatory responses to mPFC stimulation
independent of changes in baseline activity, and without consistently affecting
inhibitory responses. This suggests that OX potently influences DA neuron activity
in part by modulating responses to mPFC inputs. The authors predicted that hcrt/ox
projections to VTA may shape motivated behaviors in response to conditioned
stimuli by regulating prefrontal control of DA release.
Borgland et al. (2010) had been intensively studying the role of hcrt/ox signaling
in cellular processes underlying addiction-related behaviors and proposed a
hypothesis for the mechanisms by which hcrt/ox signaling may impart drug seeking
(see Fig. 6). Hcrt/ox signaling can promote drug-induced plasticity of glutamatergic
synapses onto DA neurons of the VTA. Additional evidence suggests that hcrt/ox
signaling can also promote drug seeking by initiating an endocannabinoid-mediated
synaptic depression of GABAergic inputs to the VTA, thereby disinhibiting
DAergic neurons. Hcrt/ox neurons co-express the inhibitory opioid peptide
dynorphin. It has been proposed that hcrt/ox in the VTA may not mediate reward
effects per se, but rather occludes the ‘anti-reward’ effects of dynorphin. Finally,
hcrt/ox signaling in the prefrontal cortex and the central amygdala is implicated in
the reinstatement of reward seeking. The same authors also argued that hcrt/ox may
also promote alcohol seeking as well as cue- or stress-induced relapse at sites
outside the VTA. OX1 receptor antagonists blocked cue-induced ethanol seeking as
well as Fos expression in the medial and orbitoprefrontal cortices.
Finally, excitatory hcrt/ox are co-expressed and potentially co-released with the
aversion-inducing neuropeptide, dynorphin. Opposing effects of these peptides
Fig. 6 Simplified diagram of pathways involved in hcrt/ox signaling. Neurohumoural information

about natural rewards is integrated by hcrt/ox neurons of the LH. Drugs of abuse may act both
locally in the LH and at hcrt/ox terminals in VTA. Exposure to rewards or reward cues increases
Fos expression and phospho-CREB in hcrt/ox neurons (inset, upper left). In the VTA (inset, upper
right) hcrt/ox can affect glutamate release onto DAergic neurons as well as stimulating them
directly via postsynaptic OX1 receptors. Within DA neurons, OX1 activation can recruit synthetic
enzymes (PLC) for endocannabinoids such as 2-AG, which can inhibit GABA release from
interneurons in a retrograde fashion. Co-released dynorphin may also modulate the excitatory
effects of its co-transmitter hcrt/ox. MOP, KOP; l-opioid, j−opioid receptors: TASK, K2P
potassium channels (from Borgland et al. (2010) with a permission)
have been proposed to facilitate reward by hcrt/ox-mediated occlusion of the

‘anti-reward’ effects of dynorphin.
Taken together, the development of novel OX1 receptor antagonists could have
excellent utility in the treatment of drug craving and relapse.
Quarta and Smolders (2014) also discussed involvements of orexigenic

hypothalamic neuropeptides, especially ghrelin, orexins and neuropeptide Y (NPY),
in regulating mesolimbic DAergic neurotransmission in rewarding, reinforcing and
incentive salient events. Motivation, reinforcement, and reward for drugs of abuse
or food is generally facilitated by the three orexigenic peptide systems, but cocaine
reinforcing properties seem not to be dependent on the hcrt/ox et al. circuit. The
authors suggest that ghrelin and NPY-mediated modulation of DA-associated
behaviors might pass, at least in part, through their action on the LH hct/ox neurons.
However, since ghrelin and NPY exert opposing effects on VTA DA cells, direct
evidence is largely lacking.
Other investigators also initiated studies of high fat intake in a binge eating
model (Valdivia et al. 2015), energy balance by leptin (Leinninger et al. 2011), and
antinociceptive actions (Okumura et al. 2015; Yazdi-Ravandi et al. 2014). These
topics are beyond the scope of this review, and we only introduced citations for
these works, without discussing the results in detail.
10 Summary
Hcrt/ox are newly discovered hypothalamic neuropeptides involved in various

fundamental hypothalamic functions, including sleep/wake, food intake, and energy
homeostasis. Immediately after the discovery of the hcrt/ox system, hcrt/ox ligand
deficiency in human narcolepsy was discovered.
Narcolepsy is a prototypical EDS with REM sleep abnormalities such as cata-
plexy, sleep paralysis and hypnagogic hallucinations. These symptoms of nar-
colepsy, together with neurochemical and pharmacological findings and their
current treatment options clearly suggest an existence of DA system deregulation in
hcrt/ox deficient narcolepsy, and these results indirectly suggest the interactions of
hcrt/ox and DA for sleep and possibly for reward and reward-motivational
behavior.
Regarding the interactions of hcrt/ox and DA, we first introduced anatomical
results that hcrt/ox neurons project densely to the VTA and SN as well as to other
monoaminergic nuclei, such as TMN, LC, raphe. However, hcrt/ox neurons exhibit
relatively few synaptic contacts with dendrites or soma of VTA DA and
VTA GABA neurons with both asymmetric and symmetric types with equal
frequency.
Hcrt/ox receptors were also shown to be expressed on both DAergic and
non-DAnergic neurons in the VTA.
These results are consistent with the functional (electrophysiological and phar-
macological) results, and hcrt/ox significantly increased Fos-ir in VTA DA neurons,
primarily in a restricted population of small-to-medium-sized DA neurons located
within the caudomedial VTA. Furthermore, within this region of the VTA, PFC-
and NAs-projecting TH-ir neurons were more likely to contain Fos-ir than were
NAc-projecting TH-ir neurons. These results provide evidence that hcrt/ox
selectively activates PFC- and NAs-projecting DA neurons within the VTA, and
suggest a potential role for hcrt/ox in PFC- and NAs-dependent cognitive and/or
affective processes via actions on the mesolimbic DA system.
Based on these results, many investigators also have studied addiction and the
role of interactions of hcrt/ox and mesolimbic DA systems in conditioned behav-
ioral responses to reward-associated stimuli. Although some of the findings are
anecdotal, it is conceivable that future research will provide scientific evidence that
hcrt/ox DA interactions play a critical role in reward-motivational behavior, high fat
intake, and antinociception.
Acknowledgments The authors thank Mari Matsumura for editing the manuscript.
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Alteration of Biological Rhythms
in Diseases of the Central Dopaminergic
System: Focus on Parkinson’s Disease
Santiago Perez-Lloret, Darío Acuña-Castroviejo,

Victor Demaria-Pesce and Daniel Cardinali
Abstract Parkinson’s Disease (PD) is characterized by profound alterations of the

circadian timing system, as evidenced by studies in animals and patients.
Alterations in activity, temperature and heart rate rhythms have been observed in
several animal models of PD. Deposition of alpha-synuclein in the hypothalamic
suprachiasmatic nuclei (SCN) (i.e, the site of central oscillator) has been detected in
transgenic mice and altered rhythms in clock genes have been reported in both the
striatum and the SCN. Furthermore, enucleation of the lateral hypothalamus,
leading to “functional blindness” aggravated parkinsonian symptoms in one PD
animal model. Disturbances in biological rhythms have also been observed in PD
patients. Of note, polymorphisms of the ARNTL and PER1 clock genes were more
frequent in PD patients compared to controls. Together with the extensive cross-talk
between the basal ganglia and SCN, these pieces of evidence suggest that distur-
bances in the circadian timing system might be part of the core features of PD and
not just a “collateral damage”. According to this view, a disturbed clockwork might
actively contribute to neurodegeneration and a chronotherapeutic approach to PD
might be considered. Melatonin, as a prototype chronobiotic agent, has been shown
S. Perez-Lloret (&)
Cardiology Research Institute, University of Buenos Aires,
National Research Council (ININCA-UBA-CONICET),
Marcelo T. de Alvear 2270, C1122AAJ Buenos Aires, Argentina
e-mail: santiagopl@conicet.gov.ar
D. Acuña-Castroviejo
Institute of Biotechnology, Biomedical Research Center,
Health Science Technology Park, University of Granada, Granada, Spain
V. Demaria-Pesce
Directeur de Recherche, Institut National de La Santé et de La Recherche Médicale
(INSERM), Paris, France
e-mail: victor.demaria@inserm.fr
D. Cardinali
Department of Teaching and Research, Faculty of Medical Sciences,
Pontificia Universidad Católica Argentina BIOMED-UCA-CONICET,
Buenos Aires, Argentina
e-mail: danielcardinali@fibertel.com.ar

DOI 10.1007/978-3-319-46437-4_6
92 S. Perez-Lloret et al.
to have some efficacy for sleep disorder treatment in PD and exhibit neuroprotec-
tion in animal models of PD. Bright light has also been effective for depression and
insomnia in PD patients. Novel chronobiological therapies might have a great
impact on the clinical management of PD.
Keywords Parkinson’s disease Biological rhythms Sleep disorders

Neuroprotection Dopamine
1 Introduction
Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting

about 1 person out of every 1000 in their fifth decade and 19 out of every 1000 in
their eighth decade or older (Pringsheim et al. 2014). Its principal clinical symptoms
are resting tremor, bradykinesia, rigidity and postural instability. Patients also
frequently display non-motor symptoms, including cognitive impairment, mood
disorders, dysautonomia and hallucinations (Chaudhuri and Schapira 2009). Sleep
alterations and other disturbances of the circadian rhythm control system also occur
frequently in PD (Videnovic and Golombek 2013).
Histopathological changes are mainly, but not exclusively, characterized by the
progressive loss of the nigrostriatal dopaminergic (DA) neurons which explain the
most typical motor symptoms (Hornykiewicz 1966). Thus, administration of
levodopa to parkinsonian patients has been considered the most effective symp-
tomatic treatment for the last 40 years (Fahn 2008).
At a cellular level, neuronal death may be preceded by a series of dysfunctional
states, including loss of redox control, alteration of lysosomal activity, abnormal
protein control mechanisms in the endoplasmic reticulum (ER) and perturbation of
the endoplasmic reticulum (ER)-Golgi trafficking mechanisms. These cellular
pathologies are closely intertwined with one of the hallmarks of the disease, namely
the abnormal accumulation of misfolded protein aggregates (Soto 2003). Lewy
bodies constitute a characteristic pathological finding. Early work identified the
immunoreactivity of the Lewy bodies with antibodies against the presynaptic
protein a-synuclein (Spillantini et al. 1997). One major target of a-synuclein is
Rab1, a key component of the endoplasmic reticulum-Golgi trafficking pathway
(Cooper et al. 2006). Endoplasmic reticulum stress has been invoked as a possible
major disruptive mechanism, leading to an adaptive reaction known as the unfolded
protein response (Ron and Walter 2007). This response may be cytoprotective when
activated to a moderate level, but is deleterious at a higher level, triggering in turn
the apoptotic death of the damaged neuron (Mercado et al. 2013; Hetz and
Mollereau 2014). PD may also be considered a synaptopathy, i.e, abnormal
synaptic connectivity compromising nigrostriatal pathways and intra-striatal
interneuronal connections, presumably most apparent at the initial stages of the
disease. Mutations in the a-synuclein gene cause familial forms of PD and dementia
with Lewy bodies. Synaptic accumulation of a-synuclein is accompanied by the
Alteration of Biological Rhythms in Diseases … 93
redistribution of the synaptic SNARE proteins SNAP-25, syntaxin-1 and

synaptobrevin-2, as well as by an age-dependent reduction in dopamine release
(Garcia-Reitbock et al. 2010).
Motor symptoms in PD have been linked to degeneration of the nigral
dopaminergic neurons and the resulting altered functioning of the basal ganglia
(Lang and Lozano 1998). The striatum is the most important input nucleus of the
basal ganglia. The principal source of afferents is the cerebral cortex, conveying
glutamatergic (Glu) excitatory synapses. The second major striatal input is DA,
stemming from the substantia nigra A9 cell group. The circuit is depicted in Fig. 1.
Extracellular DA tonically inhibits the indirect pathway by acting on D2 receptor,
while DA release by terminals from nigral dopaminergic neurons would activate
phasically the direct pathway by acting on D1 receptors (Grace 2008). According to
a widely accepted pathophysiological PD model, a reduction in the dopaminergic
tone would lead to increased activity in the indirect inhibitory pathway and reduced
activity of the direct excitatory input (Fig. 1) (Obeso et al. 2008; Wichmann and
Delong 2007). Administration of levodopa and other DA agents (such as dopamine
agonists) would thus restore the balance by stimulating the direct pathway and
inhibiting the indirect one (Grace 2008). There is also a straightforward interaction
Basal ganglia circuit under

Basal ganglia circuit in PD
normal circunstances
Cortex Cortex
Striatum Striatum
SNc
GPe VA/ GPe VA/

Rt CM Rt CM
VL VL
STN STN
GPi GPi
Brainstem Brainstem
Fig. 1 Normal basal ganglia circuit and its alteration in Parkinson’s disease and
Levodopa-induced dyskinesias. SNc Substantia nigra pars compacta. GPe/GPi Globus pallidus
pars externa or interna. STN Subthalamic nucleus. Rt Reticular thalamic nuclei. CM Centromedian
thalamic nucleus. VA/VL Ventral-anterior or lateral thalamic nuclei. Stimulatory connections are
shown in grey, while inhibitory ones are depicted in black
Fig. 2 Schematic representations of the potential cross-talk between the central biological
oscillating system and basal ganglia. Sites in which neurodegeneration or altered function have
been demonstrated in PD are signaled with a thunder. Potential connections are signaled by a
discontinued line. IGL Intergeniculate leaflet; ORX/MPOA Orexinergic neurons/median preoptical
anterior nuclei; PVN Paraventricular nuclei; SCG Superior cervical ganglion; SCN
Suprachiasmatic nuclei; SN/VTA Substantia nigra/ventral tegmental area
(see further on) between the basal ganglia and the structures responsible for cir-
cadian biological rhythms (see Sect. 2 and Fig. 2).
There are many features of PD that are unresponsive to levodopa, such as gait
disorders and cognitive impairment or dementia, indicating the involvement of
other neurotransmitter systems (Lim et al. 2009). In this regard, recent evidence
supports the occurrence of degeneration of adrenergic, serotoninergic and cholin-
ergic neurons, besides others (Lim et al. 2009). Furthermore, death of DA neurons
occurs late during the neurodegenerative process in PD. Indeed, it has been shown
that many non-motor symptoms such as REM-sleep behavior disorder, diurnal
somnolence, constipation or olfactory dysfunction precede motor dysfunction, thus
highlighting the importance of non-dopaminergic degeneration in PD (Goldman
and Postuma 2014). Alterations of biological rhythms could also precede motor
symptoms in PD (see Sect. 5.1).
In the present chapter we will review the disturbances of biological rhythms in

PD, implications for PD pathophysiology and treatment. Sleep disturbances in PD
are covered in chapters … of this book.
2 Role of DA and the Basal Ganglia in the Circadian

Timing System
Briefly, the central circadian system comprises three main elements: an endogenous
oscillator, which in mammals is located in the hypothalamic suprachiasmatic nuclei
(SCN), an entrainment agent (zeitgeber) and pathways that couple the internal clock
to rhythms in physiology and behavior (Golombek and Rosenstein 2010). The SCN
controls a number of peripheral oscillators throughout the body, which are other-
wise autonomous in terms of their rhythmic properties (Dibner et al. 2010).
DA neurotransmission, which is also important for motor control at the basal ganglia,
has been implied at several levels in the circadian system, starting with the photic input
pathway to the clock (Videnovic and Golombek 2013). In the retina, dopamine plays a
role in the regulation of sensitivity to light. Of note, neurodegeneration of the retinal
dopaminergic system has been recently demonstrated in PD patients (Adam et al. 2013).
The SCN also contains dopamine receptors, but their physiological role is unknown.
Notwithstanding, haloperidol has been found to increase expression of clock genes both
in vivo and in cultured SCN cells (Viyoch et al. 2005).
DA function in the basal ganglia also displays rhythms. Indeed, circadian
fluctuations in extracellular DA levels have been reported in the striatum and
nucleus accumbens, with maximal levels during the active phase (Hood et al. 2010;
Castaneda et al. 2004). In mice, however, DA and its metabolite, dihydrox-
yphenylacetic acid (DOPAC) exhibit opposite rhythms, the former peaking at nigh
(Khaldy et al. 2002). In another study it was observed that tyrosine hydroxylase and
cholecystokinin mRNA were upregulated in the substantia nigra and ventral
tegmental area in the course of the day (Weber et al. 2004). In the caudate and
putamen, the mRNA levels for DA D2 and adenosine 2A receptor, dynorphin, and
substance P were lower during the day than during the night, whereas the
expression of DA D1 receptor, encephalin, and somatostatin was stable (Weber
et al. 2004). These neurotransmitters are part of the indirect basal ganglia pathways,
which are overactive in PD and contributed to motor symptoms (Lang and Lozano
1998; Grace 2008). This intriguing observation suggest that the indirect inhibitory
pathway is less active during the day, when increased mobility is needed, fitting
well with predictions from the PD pathophysiological model discussed earlier.
Some results suggest that such DA circadian variations might be regulated directly
by the SCN (Mendoza and Challet 2014).
Other observations indicate that DA might also regulate the expression of PER2
clock gen in the dorsal striatum of the rat, without overt effects in the SCN (Hood et al.
2010). Furthermore, the exposure of human neuroblastoma cells (SH-SY5Y) to
1-metyl-4-phenylpyridinium (MPP+), the toxic metabolite of MPTP, increased or
decreased the mRNA levels of several clock genes in a dose-dependent manner

(Hayashi et al. 2013). In this model, inhibition of the adenosine monophosphate (AMP)-
activated protein kinase (AMPK), could revert the alteration in clock gene expression.
Light, which is one of the main inputs to the SCN and thus one of the main
controllers of biological rhythms, might also regulate functioning of the substantia
nigra, as observed in rats (Romeo et al. 2013, 2014). Exposure to bright light
induced production of neuromelanin and reduction of tyrosine hydroxylase positive
neurons in the substantia nigra. The findings were interpreted to suggest that “light
pollution” might contribute to PD development. Intraocular injections of
6-hydroxydopamine (6-OHDA), methyl-phenyl-tetrahydropyridine (MPTP) or
rotenone (which didn’t diffuse to other regions of the brain) produced motor
symptoms compatible with PD in rats (Willis et al. 2014). These results are
intriguing and may suggest that altered sensitivity to light, which is regulated by the
retinal DA pathway, might be connected with PD pathology.
There is an antagonizing relationship between DA and melatonin (Zisapel 2001).
Inhibition of DA release by melatonin has been demonstrated in specific areas of
the mammalian central nervous system (hypothalamus, hippocampus, medulla-
pons, and retina). Antidopaminergic activities of melatonin have been demonstrated
in the striatum of normal mice (Khaldy et al. 2002). In a recent study, melatonin
MT1 and MT2 receptors have been found to be expressed in human substantia
nigra, which were reduced in PD (Adi et al. 2010).
3 Alteration of Biological Rhythms in PD Animal Models
The classical PD animal models are the 6-hydroxydopamine (6OHDA)-lesioned

rodents and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated
rodent and non-human primates, while the rotenone administration is less fre-
quently used (Blesa et al. 2012). Both toxins cause the degeneration of dopamin-
ergic neurons and thus induced motor symptoms compatible with those of PD.
Toxic models are most useful to screen drugs for symptomatic treatment of the
disease; whereas transgenic or knockout models are useful for evaluating the role of
genetics in PD. The drawback of the toxic models is that most of them resemble PD
at late stages, whereas genetic animal models use either overexpression or
knock-out technology to model disease from early on.
Alterations of biological rhythms have been described in several PD animal
models (Table 1), which will be discussed in this section.
3.1 6-OHDA-Treated Rodents
One of the first studies of biological rhythms in 6OHDA-lesioned rats revealed

profound alterations (Ben and Bruguerolle 2000). Bilateral lesions produced mod-
ifications of heart rate, temperature and activity rhythms, with a significant decrease
Table 1 Alteration of biological rhythms in PD animal models

Findings
Activity Temperature Heart rate Clock genes Other
6-OHDA-treated rodents
Ben and # MESOR, # MESOR, # MESOR & – –
Bruguerolle phase phase amplitude,
(2000) advance advance phase advance
Slack et al None None # MESOR – –
(2010)
Hood et al – – – Blunted No alterations in the
(2010) PER2 SCN
rhythm in
striatum
MPTP-treated rodents
Leng et al Probable – – – –
(2004) Inversion
Fifel et al None – – – –
(2013)
Hayashi et al Disturbed Disturbed – Disturbed in –
(2013) striatum
Rotenone-treated rodents
Lax et al # MESOR # MESOR – – –
(2012) & amplitude
Mattam and – – – Abolished Abolition of
Jagota (2015) in the SCN melatonin and 5HT
rhythms
MPTP-treated primates
Barcia et al # MESOR – – – –
(2004) and
amplitude
Fifel et al Abolished – – – Hormonal rhythms
(2014) in LL unaltered in LL
Khaldy et al – – – – Melatonin + L-
(2003) deprenyl "
hypoactivity and "
striatal DA
Transgenic mice
Kudo et al # MESOR – – None Altered firing
(2011) patterns in SCN
Fifel et al Disrupted
(Fifel and in DD
Cooper 2014)
Other
MPTP-treated # amplitude and
dogs (Hineno inversion of urine
et al. 1992) production rhythm
DA Dopamine; DD Continuous darkness; LL Continuous light; SCN Suprachiasmatic nuclei; MESOR
Midline estimating statistic of rhythm (i.e. mean daily values)
of the mean daily values as well as a phase advance. Heart rate rhythms also showed
decreased amplitude. Rats were maintained in Light:Darkness (L:D) 12:12.
The contribution of enucleation of the lateral hypothalamus to parkinsonism was
explored in the 6OHDA-lesioned rats in L:D 12:12 (Willis et al. 2008). This
manipulation disrupts the retino-hypothalamic tract and thus produces “functional
blindness” leading to altered biological rhythms. Hemi-enucleation ipsilateral to the
side of the 6OHDA lesions produced impairment of horizontal movement, limb
retraction, ambulation and spontaneous or levodopa induced turning. This impair-
ment was more severe than in rats with unilateral 6OHDA lesions alone. These
results highlight the potential role of the alterations of the central oscillator in the
pathophysiology of PD, as discussed earlier.
Alterations of autonomic rhythms were explored in eight unilateral
6-OHDA-lesioned rats in L:D 12:12, six with sham lesions and 16 without surgery
(Slack et al. 2010). Daily mean heart rate values were reduced in lesioned animals
with a notorious decrease during the night. No differences in activity or body
temperature rhythms were detected.
To explore how changes in endogenous levels of dopamine would affect the
normal rhythm of PER2 (one of the genes that control rhythms at a cellular level) in
the dorsal striatum, mRNA levels were measured in 6-OHDA treated rats and
saline-treated animals (Hood et al. 2010). The 6-OHDA injection severely blunted
the rhythm of PER2 expression in the lesioned hemisphere, but did not affect the
normal PER2 rhythm on the intact side or in the SCN. Injections of 6-OHDA to the
third ventricle, which would produce a widespread lesion of dopaminergic fibers
brought about similar results (Gravotta et al. 2011).
The effects of antiparkinsonian medications on biological rhythms in
6OHDA-lesioned rats have been studies in two trials. In the first one, lesioned rats
maintained in L:D 12:12 were treated with subcutaneous levodopa 100 mg/kg/day
(ie, a supratherapeutic dose) for 7 days (Simon et al. 2000). Levodopa increased mean
daily values of temperature and heart rate and increased the amplitude of temperature
but decreased the amplitude of heart rate. Thus, levodopa corrected some of the
alterations of diurnal rhythms of temperature and heart rate (Ben and Bruguerolle
2000). A second study with the same experimental paradigm confirmed the effects of
levodopa (Boulamery et al. 2010). Authors suggested that circadian infusions of
levodopa mimicking normal dopamine rhythm may be able to offer further benefits.
3.2 MPTP-Treated Rodents
Effects of MPTP lesions on wheel running activity was explored in C57bl/6 mice in
L:D 12:12 (Leng et al. 2004). As expected after MPTP treatment C57bl/6 mice
showed reduced running wheel activity which lasted during the entire active phase
(20:00–08:00 h), recovered to baseline levels in the following two to four days and
remained stable up to the end of the experiment. Notably, a complete inversion of
the circadian rhythm was during the acute phase, which was not adequately char-
acterized by the authors.
Fifel and colleagues explored the effects of MPTP lesions in the same mice
model (Fifel et al. 2013). Activity rhythms and locomotor activity were assayed
under light-dark cycles, constant darkness, or constant light, re-entrainment to shifts
of the light-dark cycle, and a behavioral masking paradigm. No changes were
observed. These results are in contrast to those of Hayashi and colleagues, who
could show alterations of body temperature and locomotor activity rhythms in a
similar PD model (Hayashi et al. 2013).
Of note, the addition of ATP to the drinking water of MPTP-treated mice
attenuated neurodegeneration in dopaminergic neurons, suppressed AMPK acti-
vation and prevented circadian disruption. These results along with the findings that
inhibition of the AMPK could revert the alteration in clock gene expression in
neuroblastoma cells (Hayashi et al. 2013), suggest that AMPK is related to circa-
dian dysfunction in MPTP treated mice. It is not clear how these data can be
translated to humans. Further animal and clinical studies on the potential efficacy of
AMPK inhibitors for the treatment of circadian dysfunction in PD are needed.
Khaldy and colleagues studied the effects of melatonin and L-deprenyl, a
monoaminooxidase (MAO) B enzyme inhibitor in MPTP-treated C57bl/6 mice
(Khaldy et al. 2003). Melatonin alone did not alter hypoactivity after MPTP, but
synergized with L-deprenyl did enhance locomotor activity in treated animals.
Melatonin also synergized with L-deprenyl recovered DA levels, and tyrosine
hydroxylase activity; most important, melatonin alone recovered normal mito-
chondrial complex I activity, and (LPO) levels affected by MPTP. These data point
to a primary effect of melatonin to recover mitochondrial function, reducing
oxidative damage in the striatum.
3.3 Rotenone-Treated Rodents
Rotenone is a potent inhibitor of mitochondrial complex I, causing degeneration of

the DA neurons. In one study, long-term subcutaneous administration of rotenone
significantly reduced mean daily locomotor activity, mean body temperature and
amplitude under L:D 12:12 (Lax et al. 2012). Lower interdaily phase stability, and
higher rhythm fragmentation were also observed correlating with motor deficits.
These data raise the possibility that at least a part of rhythm alterations might be
related to a masking effect from motor dysfunction. In another study, a complete
abolition of serotonin and melatonin rhythms and circadian expression of SCN
clock genes, was observed (Mattam and Jagota 2015), which makes the masking
effect of motor disability on rhythm alterations in this PD animal model less likely.
Early administration of melatonin together with rotenone could thus prevent
changes in clock genes induced by the toxin. Melatonin and its metabolite
N1-acetyl-5-methoxykynuramine, were shown to prevent mitochondrial iNOS
induction and bioenergetic recovery in MPTP-induced Parkinsonian mice (Tapias
et al. 2009).
In another study melatonin potentiated dopamine depletion in the striatum

(Tapias et al. 2010) contradicting a whole body of evidence for the neuroprotective
property of melatonin.
3.4 MPTP-Treated Non-human Primates
The effects of MPTP administration to non-human primates are usually measured

visually by using validated scales. Quantification of disability could also be done
telemetrically as reported by Barcia et al. (2004). Recording were done 15 days
after recovery from surgery. Animals were maintained in L:D 12:12 without any
anti-parkinsonian treatments. Although circadian motor activity was not formally
explored the investigators observed a reduction of main daily values and amplitude
without overt modifications in the phase. Another study confirmed these results in
L:D (Fifel et al. 2014). Furthermore, when challenged by exposure to constant light,
controls retained locomotor activity and hormonal rhythms that free-run with stable
phase relationships whereas lesioned animals showed altered circadian rhythm with
no changes in hormonal rhythms.
3.5 Transgenic Models
Kudo et al (2011) studied circadian dysfunction in a transgenic mouse PD model.

One of the most important findings of this study is overexpression of
alpha-synuclein in the SCN. The animals displayed lower night-time activity and
greater fragmentation in the wheel-running activity. Mice were followed for up to
one year, during which activity worsened progressively both in the mutant and the
control wild type mice. When placed in a L:D 11:1:11:1 (ie, a skeleton photope-
riod), rhythms were less pronounced. When maintained in constant darkness, the
phase including a 6-h phase advance was not altered in the mutant mice. Finally, no
major alteration of the expression of clock gene expression was noticed, but
spontaneous neural activity was reduced in the SCN of mutant mice. The authors
suggested that a weakened circadian timing system might be a core feature of PD.
Biological rhythm disturbances have also been explored in the transgenic
MitoPark mouse model of PD, which is based on the specific deletion of the gene
encoding for the mitochondrial transcription factor A (Tfam) in DA neurons (Fifel
and Cooper 2014). Animals were shifted from a L:D 12:12 condition to constant
darkness, constant illumination with dim-light and constant high-light illumination.
In LD, MitoPark mice exhibited daily rest/activity rhythms which declined with
age, coupled with an increased fragmentation of day/night activities. When trans-
ferred to constant darkness condition, wild-type controls retained robust
free-running circadian locomotor rhythms, whereas in MitoPark mice, locomotor
rhythms were severely disturbed or completely abolished. Re-exposure to a
light/dark cycle completely restored daily locomotor rhythms. MitoPark animals

however, responded to phase shifting more intensely than controls, which was
thought to be due to a masking effect of light that was also observed when animals
were exposed to a L:D 1:1 photoperiod.
3.6 Other Animal PD Models
Circadian diurnal rhythms of urinary volume and creatinine vasopressin, aldos-

terone and renin activity in plasma were measured under L:D 12:12 in Parkinson’s
disease model induced by MPTP in dogs (Hineno et al. 1992). Rhythm of urine
volume showed reduced mean daily values, reduced amplitude and inversion of the
phase, with maximal values during the night inactive period. These alterations
could not be explained by a difference in water drinking patterns. However,
administration of levodopa partially normalized these changes in urinary volume
and alterations in vasopressin rhythms.
Zebrafish as a model of PD has a series of advantages including a
well-characterized DAergic system, with b- and gamma1-synuclein required for
spontaneous movements, with a similar role to those in humans (Milanese et al.
2012). Recently, it has been shown for the first time that melatonin treatment to
zebrafish embryos not only prevents but fully recovers zebrafish parkinsonian
phenotype induced by MPTP. This treatment promotes mitochondrial bioenergetics
and ATP production, and enhances expression of mitochondrial related genes
inhibited by MPTP (unpublished observation).
3.7 Summary
Animal PD models show profound alterations in biological rhythms of activity,

temperature and heart rate, as summarized in Table 1. Results from different animal
models were heterogeneous, and this might represent differences in the models or
protocols themselves. Therefore, assessment of biological rhythms should probably
be performed in several animal models in order to obtain meaningful conclusions.
Interestingly, alterations in the expression of clock genes were found in the striatum
and in some cases in the SCN, thus confirming the alteration of the circadian timing
system in PD, which might a core feature of the disease. Furthermore, enucleation
of the lateral hypothalamus, which produces “functional blindness” increased the
severity of the motor symptoms after 6OHDA lesions (Willis et al. 2008), thus
suggesting that alterations of the circadian timing system might be an integral part
of PD, significantly contributing to disability. Notwithstanding, the exact mecha-
nism by which light might affect motor functions remains unknown. This
hypothesis is supported by the findings of deposition of alpha-synuclein in the SCN
of a transgenic mouse model (Kudo et al. 2011).
Administration of levodopa could revert some alterations in biological rhythms

(Simon et al. 2000). These finding strongly suggest that circadian alterations in PD
are connected with DA pathology. Melatonin was able to reduce the impact of
rotenone on clock genes (Mattam and Jagota 2015) and the severity of parkinsonian
symptoms in mice treated with 6OHDA (Dabbeni-Sala et al. 2001). These results
suggest that melatonin might be useful in PD patients to treat chronobiological
alterations and to protect dopaminergic neurodegeneration.
4 Human Studies in PD Patients
In this section, we will review the compromise of the circadian timing system in PD
patients, as discussed in several. recent review articles (Videnovic and Golombek
2013; Videnovic and Willis 2016; Willison et al. 2013).
4.1 Clock Genes
The circadian clock is primarily composed of a cell-autonomous transcriptional

feedback loop (Harms et al. 2004). In mammals the circadian clock mechanism is
made up of two interlocking, regulatory feedback loops and some important clock
genes include: BMAL1 and 2, PER1 and 2, CRY1 and 2. Disturbances in the
expression of clock genes in PD patients have been reported in a number of clinical
studies. The expression profiles of PER1 and BMAL1 clock genes in leukocytes for
12 h during the evening, overnight and morning have been assessed in PD patients
and age/sex-matched healthy controls (Cai et al. 2010). Patients were studied in
their normal L:D cycle (bed time at 22 h and awake time at 6:30 h) collecting blood
samples while the patients slept in the laboratory. Normally abundant BMAL1 was
significantly lower in PD patients than in control subjects at 21:00, 12:00 and
06:00 h, without overt changes in PER1 expression. BMAL1 expression correlated
with PD severity at certain time points but it is not clear up to which point these
alterations resulted from a disturbance of the biological clocks or if they were
related to other factors (eg, dopaminergic treatment). In a subsequent report, bio-
logical samples from these patients were used to assess expression of Bmal2, Clock,
and Dec1. The expression of Bmal2 was found to be significantly lower in PD at
21:00 and 12:00 h, without any further change (Ding et al. 2011). Alterations in
peripheral Bmal1 rhythmicity were noted in early PD patients (Breen et al. 2014).
Gu et al. (2015) in an analysis of polymorphism in eight critical clock genes
(NPAS2, CLOCK, RORB, ARNTL, CRY1, CRY2, PER1, NR1D1) in a case
control study of Han chinese 1253 PD patients and 1342 controls. Polymorphism in
ARNTL and Per1 genes were more frequent in PD than in controls. These authors
also found that polymorphism of the ARNTL was related to a tremor-dominant PD

form, whereas polymorphism of Per1 gene was related to Postural-Instability Gait
Disorder (PIGD) form.
4.2 Brain Monoamine Rhythms
In attempt to further characterize alterations of biological rhythm in PD, some

studies focused on rhythms of brain monoamine contents. Circadian variation in
dopamine and related compounds in human cerebrospinal fluid, withdrawn con-
tinuously for 22 h from an implanted lumbar intradural catheter, was characterized
in three PD patients and three healthy controls (Poceta et al. 2009). Although the
sample was small for statistical analysis, the authors suggested an inversion of the
daily dopamine rhythm in PD patients. Seasonal variations in striatal fluorodopa
(FDOPA) uptake, a marker of dopamine synthesis, were characterized in a group of
109 Finnish patients (Kaasinen et al. 2012). FDOPA uptake was reduced by 15 %
in patients assessed during spring-summer, thus indicating reduced DA synthesis,
paralleling changes observed in healthy volunteers (Eisenberg et al. 2010).
Histamine is a wake-promoting monoamine, with a diurnal rhythm peaking
during daytime. The mRNA expression of histidine decarboxylase (HDC), the rate
limiting enzyme for histamine production in the tuberomammillary nucleus has
been recently explored in postmortem human hypothalamic tissue of 31 patients
with neurodegenerative disease (15 with PD) and 33 controls, covering the full 24-h
cycle with respect to clock time of death (Shan et al. 2012). A phase advance in the
mRNA rhythm was noted in patients with neurodegenerative disease compared to
controls which may explain in part the presence of sleep disturbance and daytime
sleepiness in PD (Chaudhuri and Schapira 2009), however, use of a variety of
medications and inclusion of small number of patients limit this interpretation.
4.3 Melatonin and Light Sensitivity
Melatonin, which occurs ubiquitously in nature, is a remarkable molecule with

diverse physiological functions, including regulation of biological rhythms, scav-
enger of oxidative free radicals and immunomodulation (Hardeland et al. 2015;
Reiter et al. 2010). In this section, we will review alterations of melatonin rhythm
and possible neuroprotective effect of melatonin in some animal PD models
(Dabbeni-Sala et al. 2001; Naskar et al. 2015; Willis and Armstrong 1999), as well
as potential therapeutic efficacy for sleep disorders in PD patients (Srinivasan et al.
2011; Zhang et al. 2016).
Dim light melatonin onset and area under the melatonin curve (measured in
saliva samples) have been recently assessed in 28 controls, 13 de novo PD (ie,
without medications), and 16 patients on antiparkinsonian dopaminergic treatments
(Bolitho et al. 2014). There were no differences in the time of melatonin onset, but
the area under the curve was significantly higher in treated PD as compared to both
untreated PD patients and controls. PD treated patients did not differ from their
untreated counterparts in terms of PD severity, depression scores, age, or gender.
These results contrast with previous findings of normal melatonin levels coexisting
with a phase advance of the rhythm in levodopa-treated PD patients (Fertl et al.
1991) but not in de novo patients (Fertl et al. 1993). While this difference might
have been related to the way in which melatonin onset was measured, both studies
suggest that alterations of melatonin might be restricted to patients on dopaminergic
replacement therapy.
In another study of 239 newly diagnosed patients (mean time from onset of
symptoms to diagnosis 2.2 months) of whom 42 % were on dopaminergic
replacement therapy, area under the curve of the melatonin rhythm was found to be
significantly reduced as compared to controls (Breen et al. 2014). Reduced total,
daytime and nighttime melatonin levels were also found in a sample of 20 patients
with more advanced disease compared to the previous study (Videnovic et al.
2014). Furthermore, patients with daytime somnolence have lower melatonin levels
compared to PD without somnolence. These results contrast with previous reports,
and the reasons for such divergence remain undetermined. Videnovic et al. (2014)
suggested that methodological differences among the trials might be the cause for
this divergence. In particular, experimental protocols used in the previous studies
did not control for environmental conditions and behaviors, which are known to
affect melatonin rhythm. Further studies are needed to confirm these conclusions.
Circadian rhythm in light sensitivity has been assessed in PD and matched
healthy controls (Struck et al. 1990). Subjects remained at the clinical research
center during the whole period of study and they were subjected to their normal L:D
cycle. Results suggest reduced light sensitivity which was maximal at 2:30 p.m.
The efficacy of bright light therapy, which is supposed to activate the circadian
system by inhibiting melatonin secretion, has been assessed in some PD trials.
Willis and colleagues reported the results of an open-label, retrospective study
comparing PD with controls without other neurological diseases (Willis et al.
2012). Patients who continued on bright light therapy for the whole study period
(eight years) had lower depression and insomnia scores compared to those that quit
early or were not compliant. No differences in motor symptoms were observed, as
opposed to the results of a previous case series of 12 PD patients by the same
authors (Willis and Turner 2007).
Effects of bright light have also been assessed in a randomized, controlled study
in 36 PD patients (Paus et al. 2007). Illuminance was 7500 lx in the active treat-
ment group and 950 lx in the placebo group. Bright light led to significant
improvement of tremor, Unified PD Rating Scale part I (mentation and behaviour),
part II (Activities of daily living) and part IV (levodopa-related motor complica-
tions), and depression in the active treatment group but not in the placebo group.
4.4 Body Temperature
Rhythms in body temperature have been assessed in PD in some studied. Eight

controls and seven PD patients were monitored continuously for 48 h in a
temperature-controlled room, at constant bed rest with controlled food intake and
fixed light-dark schedule (Pierangeli et al. 2001). Temperature was continuously
monitored by a rectal temperature every two min for the whole study period. No
differences between groups were observed. In another study employing the same
experimental paradign, body temperature rhythms were assessed in 24 PD patients
without depression and six with depression (Suzuki et al. 2007). Depressive patients
showed worst sleep quality and reduced amplitude of the temperature rhythm with
higher minimum nocturnal values. Furthermore, in two out of the six depressed
patients, the rhythm was absent. Reduced amplitude of this rhythm along with
lower mean values was also found in a group of non-depressed PD patients com-
pared to controls. Such alterations correlated with the severity of self-reported
Rapid Eye Movement Sleep Behaviour Disorder symptoms, reduction in the per-
centage of REM sleep and prolonged sleep latency (Zhong et al. 2013). The authors
hypothesized that altered temperature rhythms and REM pathology could be related
to the affectation of the ascending arousal system in the midbrain and pons.
4.5 Endocrine Rhythms
Cortisol diurnal rhythm was explored in 12 PD patients and 10 healthy

age-matched controls (Hartmann et al. 1997). Patients were admitted to the hospital
the night before the study and remained in supine position throughout the study
period. Daytime napping was not allowed and meal, and bed times were fixed.
Twenty-four hour blood sampling was performed from starting at 18:00 h at 15-min
intervals. Mean cortisol and mass of cortisol secreted per burst were higher in PD
than in controls, especially during the nighttime and morning. These changes were
independent of depression and were replicated by Breen et al. (2014).
Tolson and colleagues undertook a descriptive study to explore the variation of
parkinsonian symptoms across the menstrual cycle in 19 PD women (Tolson et al.
2002). Fifteen women reported worsening problems during the cycle, with
increasing pain, fatigue, worsening of PD symptoms, and reduction in medication
effectiveness.
Serum growth hormone (GH), thyroid-stimulating hormone (TSH), as well as
leptin, adiponectin and resistin prolactin (measured every 10 min for 24 h) rhythms
showed no alterations in eight medication-free PD patients and eight age-, sex- and
body mass index-matched controls (Aziz et al. 2011a, b).
4.6 Activity-Rest Rhythms
Activity-rest rhythms are intimately connected with sleep, which is known to be

altered in PD (Chaudhuri and Schapira 2009). Activity rhythm can be easily
measured by actigraphy, and this has been done in some studies. In one study, PD
patients showed reduced amplitude and increased intraday variability (Whitehead
et al. 2008) which were worse in patients with hallucinations. Our group has also
analyzed activity-rest rhythm in control and naïve- and treated-PD patients
(Perez-Lloret et al. 2010) showing that patients on dopaminergic therapy had
shorter sleep duration and an earlier onset of the diurnal activity phase. Interday
variability at the onset and offset of sleep was increased in PD patients, independent
of treatment.
4.7 Blood Pressure and Heart Rate
Autonomic function is altered in PD and this leads to orthostatic hypotension in

many cases (Goldstein 2003; Goldstein et al. 2002; Stuebner et al. 2013). Therefore
it is not surprising to find altered blood pressure rhythm with elevated nighttime
values in PD along with autonomic dysfunction (Berganzo et al. 2013; Ejaz et al.
2006; Plaschke et al. 1998). Increased hyperintensities in brain white matter (Oh
et al. 2013), and psychosis in PD (Stuebner et al. 2015) may be related to nocturnal
hypertension, which should be treated in PD to avoid further brain damage. Both
autonomic failure and psychosis are known adverse reactions to dopaminergic
therapy, and levodopa equivalent dose was higher in non-dippers, thus suggesting a
possible explanation for this link. In another study, depression was associated with
nocturnal blood pressure dipping (Vetrano et al. 2015).
The findings of a study assessing 24-h variations in heart rate variability appear
to confirm the suggestion that altered BP rhythms are not related to a disturbance in
rhythm control. In this study, the high frequency and low frequency components of
the heart rate variability, reflecting the parasympathetic and sympathetic input to the
heart were diminished during the whole period in PD, without major differences in
the diurnal and nocturnal recordings (Niwa et al. 2011). These results were repli-
cated by other authors (Pursiainen et al. 2002).
4.8 Summary
Results of clinical studies confirm the importance of chronobiological alterations in

PD. Not only the alterations in expression of clock genes, but also polymorphism of
some of these genes have been noted in PD patients. The finding of polymorphism
preceding the onset of PD may explain daytime somnolence preceding PD

(Goldman and Postuma 2014).
Findings regarding melatonin deserve a final word. Both reduced, and increased
and even normal levels have been found in PD patients. Some studies connected
increased levels to dopaminergic treatment, but not in others. Melatonin has
dopamine-antagonizing property (Zisapel 2001), and thus increased levels would
account for the worst outcome (Willis 2008). Additionally, melatonin is a potent
antioxidant and reduced circulating levels would fit well with the theory of
increased oxidative stress contributing to neurodegeneration in PD (Srinivasan et al.
2011). Further studies are needed to shed light on this conflicting body of evidence.
5 Chronotherapeutic Aspects in PD
Levodopa is the “gold standard” antiparkinsonian treatment (Birkmayer and

Hornykiewicz 1998), but its use is complicated by the emergence of motor com-
plications (i.e, dyskinesias and/or motor fluctuations) (Fabbrini et al. 2007; Nutt
2001). Levodopa is has a short plasma half-life explaining a short-duration motor
response to the drug, which is superimposed on the long-duration response, related
to the storage of dopamine in striatal synaptic terminals (Nutt 2008). It has been
proposed that motor fluctuations appear when the long-duration response is
exhausted, which might be related to degeneration of DA neurons with disease
progression (Nutt 2008).
There is some evidence that there might be a circadian variation in the phar-
macokinetic and pharmacodynamics of levodopa. Indeed, Bonuccelli et al. (2000)
reported diminished motor response to levodopa in levodopa-treated patients but
not in naïve patients. No significant variations were observed in levodopa phar-
macokinetics, with the exception of the accumulation of 3-O-methyldopa (3OMD),
which competes with levodopa for the transporter at the blood-brain barrier. As
3OMD levels didn’t correlate with motor response, the authors suggested that daily
variations in response to levodopa were not connected with pharmacokinetic
modifications. In another study, worsening in the afternoon of the motor response to
apomorphine, a dopamine agonist, was demonstrated in 10 PD patients (Monge
et al. 2004). These results further suggest that daily variations in response might be
related to pharmacodynamics factors at the striatal level. Despite variations in
levodopa pharmacokinetics the delayed absorption of levadopa during nighttime,
may be due to delayed gastric emptying (Nyholm et al. 2010). Circadian variability
in oral absorption has also been demonstrated for nebicapone, a catechol-O-
methyltransferase inhibitor (Almeida et al. 2010). It can therefore be concluded that
there exist circadian variations in the pharmacokinetics and pharmacodynamics of
dopaminergic drugs, which might justify a chronotherapeutic approach in the
treatment of parkinsonian patients.
6 Future Directions
There is an extensive body of evidence revealing important disturbances in the

circadian timing system in PD, both in experimental and clinical studies (Tables 1
and 2). Furthermore, the importance of the cross-talk between the circadian timing
system and the basal ganglia is self-evident (Fig. 2). The physiological meaning of
this cross-talk remains obscure, but its importance in pathology has been high-
lighted by the findings of increased parkinsonism severity in animal PD models
with lesions of the lateral hypothalamus, leading to “functional blindness” and
altered circadian timing function (Willis et al. 2008). These observations suggest
that not only neurodegeneration in PD might affect the circadian system as “col-
lateral damage” but also the altered function may actively contribute to PD
development. The molecular clockwork regulates mitochondrial function, reactive
oxygen species homeostasis, DNA repair and immune response (Willison et al.
2013). Dysfunction of this timing system is likely to contribute to chronic
Table 2 Summary of alterations of biological rhythms in PD patients

Rhythm Findings
Clock genes Altered expression of BMAL1 and PER1 (Cai et al. 2010; Breen
et al. 2014), BMAL2 (Ding et al. 2011)
SNPs in ARNTL and PER1 were more frequent in PD (Gu et al.
2015). The former was related to tremor and the latter to PIGD
Dopaminergic Possible inversion of CSF dopamine rhythm (Poceta et al. 2009)
neurotransmission Seasonal rhythms in PD and controls (Kaasinen et al. 2012)
Melatonin production increased circulating levels, (Bolitho et al. 2014) normal levels with
phase advances (Fertl et al. 1991) or reduced levels (Breen et al.
2014; Videnovic et al. 2014)
Light sensitivity Reduced in PD, especially at 2:30 PM (Struck et al. 1990). Bright
light showed some efficacy for insomnia and depression (Paus et al.
2007)
Body temperature No disturbances in general PD populations (Pierangeli et al. 2001),
but altered in patients with depression (Suzuki et al. 2007)
Hormones Increased cortisol secretion (Breen et al. 2014; Hartmann et al.
1997)
Significant impact of menstrual hormonal cycle in PD symptoms
(Tolson et al. 2002)
No disturbances of GH, TSH, prolactin rhythms (Aziz et al. 2011),
leptin, adiponectin and resistin (Aziz et al. 2011)
Activity-rest reduced amplitude and increased intraday variability (Whitehead
et al. 2008)
shorter sleep duration and an earlier onset of the diurnal activity
phase in patients on dopaminergic therapy (Perez-Lloret et al. 2010)
Cardiovascular Nighttime hypertension (Berganzo et al. 2013; Ejaz et al. 2006)
related to autonomic dysfunction
CSF Cerebrospinal fluid; PIGD Postural-instability gait disorders; SNPs Single nucleotide
polymorphisms
inflammation, mitochondrial dysfunction, and DNA damage. In line with this

hypothesis, deposition of alpha-synuclein has been shown in transgenic animal
models (Kudo et al. 2011).
This view is reinforced by the findings of the increased frequency of poly-
morphisms in some clock gens in PD patients compared to controls (Gu et al.
2015). These intriguing results need to be confirmed in prospective cohorts and
their contribution to PD risk needs to be better quantified. Another interesting line
of research is the finding that excessive exposure to light might contribute directly
to neurodegeneration (Willis et al. 2014). James Parkinson described PD in the
beginning of the 19th century (Parkinson 2002), coinciding with the emergence of
artificial lighting. It is very tempting to hypothesize that lighting in
non-physiological conditions might have contributed to the burst of this disease in
modern society. In summary, the view of disturbed biological rhythms in PD as
“collateral damage” can no longer be maintained. Rather, alterations in the circa-
dian timing system might be considered among the core features of the disease.
This view has profound implications for therapeutics, as it opens a vast and
previously unexplored realm. At present very little chronotherapeutic approach is
available for use in PD. Melatonin is a chronobiotic that might have therapeutic
application in PD, but further data are needed (Srinivasan et al. 2011). Some
promising results have also been observed with bright light, which should be
replicated in larger samples (Paus et al. 2007). Identification of new drug targeting
candidates involving clock genes or time-dependent administration strategies (i.e,
chronotherapy) may become a very active field in the near future (Mendoza and
Challet 2014). DA activity is rhythmic over 24 h underphysiological conditions,
and, therefore normalizing the daily rhythm of extracellular dopamine levels at the
right time of the day may improve mental health and well-being of patients.
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Parkinson’s Disease and Sleep/Wake
Disturbances
Todd J. Swick and William G. Ondo
Abstract Parkinson’s disease (PD) has traditionally been characterized by its

cardinal motor symptoms of bradykinesia, rigidity, resting tremor, and postural
instability. However, PD is increasingly recognized as a multidimensional disease
associated with myriad non-motor symptoms including autonomic dysfunction,
mood disorders, cognitive impairment, pain, gastrointestinal disturbance, impaired
olfaction, psychosis, and sleep disorders. Sleep disturbances, which include sleep
fragmentation, daytime somnolence, sleep-disordered breathing, restless legs syn-
drome (RLS), nightmares, and rapid eye movement (REM) sleep behavior disorder
(RBD), are estimated to occur in 60–98 % of patients with PD. For years,
non-motor symptoms received little attention from clinicians and researchers but
now these symptoms are known to be significant predictors of morbidity, quality of
life, costs of disease, and rates of institutionalization. A discussion of the clinical
aspects, pathophysiology, evaluation techniques and treatment options for sleep
disorders encountered with PD are presented.
Keywords Non-motor Pathophysiology Synuclein Sleep disorders

Dopamine
T.J. Swick (&)

University of Texas School of Medicine-Houston, 7500 San Felipe,
Suite 525, Houston, TX 77063, USA
e-mail: tswick@houstonsleepcenter.com
T.J. Swick
Apnix Sleep Disorders Centers, Houston, TX, USA
T.J. Swick
The Sleep Center at North Cypress Medical Center, Cypress, TX, USA
W.G. Ondo
Methodist Neurological Institute, Houston, USA

DOI 10.1007/978-3-319-46437-4_7
116 T.J. Swick and W.G. Ondo
1 Introduction
Parkinson’s disease (PD), is a worldwide heterogeneous neurodegenerative disease

that has traditionally been characterized by its cardinal motor signs of bradykinesia,
rigidity, resting tremor, and postural instability. However, PD is increasingly rec-
ognized as a multidimensional disease associated with myriad non-motor symptoms
including autonomic dysfunction, mood disorders, cognitive impairment, pain,
gastrointestinal disturbance, impaired olfaction, psychosis, and sleep disorders
(Barone et al. 2009; Martinez-Martin et al. 2007). Whereas motor symptoms of PD
mostly result from the loss of dopamine cells, non-motor symptoms have a far less
clear-cut pathophysiologic basis. Sleep disturbances, which include sleep frag-
mentation, daytime somnolence, sleep-disordered breathing, restless legs syndrome
(RLS), nightmares, and rapid eye movement (REM) sleep behavior disorder (RBD),
are estimated to occur in 60–98 % of patients with PD (Tandberg et al. 1998; Lees
et al. 1988; Thorpy 2004; Friedman and Chou 2004). For years non-motor symp-
toms received little attention from clinicians and researchers (Shulman et al. 2001,
2002), but now these symptoms are known to be significant predictors of quality of
life, costs of disease, and rates of institutionalization (Committee 2002; Aarsland
et al. 2000; Witjas et al. 2002; Schrag et al. 2000; Findley et al. 2003; Hagell et al.
2002; Pressley et al. 2003).
This chapter will explore normal sleep/wake physiology, neuroanatomy, and
neurochemistry, following which we will then discuss sleep/wake abnormalities
that have been associated with PD, discussing pathophysiology, clinical presenta-
tions, and long-term implications for diagnosis and management. The role of
dopamine in the physiology and pathophysiology of sleep disturbances in PD will
be reviewed.
We will look at the normal sleep/wake control mechanisms that result in onset
and maintenance of wakefulness via circadian/homeostatic controls that permit
transition into sleep with the subsequent ultradian cycling of Non REM and REM
sleep; and contrast it to the impaired sleep architecture/cycling that commonly
accompanies PD.
Sleep/Wake Disorders covered in connection with Parkinson’s Disease include
the following:
1. Insomnia
2. Excessive Daytime Sleepiness
3. Circadian Rhythm Disorders
4. Restless Legs Syndrome
5. Periodic Limb Movements
6. REM Sleep Parasomnias
a. REM Sleep Behavior Disorder
b. Other REM parasomnias
7. Sleep Disordered Breathing.
Parkinson’s Disease and Sleep/Wake Disturbances 117
2 Normal Sleep/Wake Physiology and Pathophysiology

of Insomnia and Excessive Daytime Sleepiness in PD
We normally exist in three states: wakefulness, non-REM sleep, and REM

sleep. This schema is present in nearly all animal species. Wakefulness is charac-
terized by well-recognized patterns on surface EEG recordings. Alpha activity (8–
12 Hz waves of <50 µV amplitude) occurs when individuals are resting with their
eyes closed. The rhythms are most evident in the parieto-occipital areas of the head
and are attenuated or blocked by attention, eye opening or mental effort. The
transition to and from sleep is a neurochemical and physiologic continuum, how-
ever, criteria have been established that allow for the clinical and research sepa-
ration of individual sleep states in a reproducible fashion.
Wakefulness is defined polysomnographically by the presence of >50 % of a
30-s recording epoch containing alpha rhythm predominantly over the occipital
region with eyes closed. Sleep stage N1 (Non-REM sleep) is defined as attenuation
or drop-out of a-rhythm replaced by at least 50 % of the 30 s recording epoch
exhibiting low amplitude, mixed frequency EEG and/or activity in the range of 4–
7 Hz, vertex sharp waves or slow eye movements. Stage N2 of Non-REM sleep
starts with the appearance of K-complexes and/or the presence of one or more trains
of sleep spindles seen during a 30 s recording epoch. Stage N3 (also called
slow-wave sleep) starts when 20 % or more of the recording epoch contains delta
waves of 0.5–2 Hz with a peak-to-peak amplitude of >75 µV measured over the
frontal regions.
REM sleep (Stage R) is defined as presence of low amplitude, mixed frequency
EEG frequently associated with the appearance of “saw-tooth waves” which are
trains of sharply contoured, triangular or serrated 2–6 Hz waves, maximal in
amplitude over the central head regions) low chin muscle tone and rapid eye
movements (Berry et al. 2015). REM sleep is also called paradoxical sleep because
its EEG patterns and frequencies are similar to those of wakefulness, except there is
loss of muscle tone (atonia) and rapid “jerky” eye movements. The autonomic
nervous system in REM switches from predominantly parasympathetic tone
(characteristic of Non REM sleep) to predominantly sympathetic tone with an
increase in average heart and respiratory rate and greater heart rate variability
(Mancia 1993) (Fig. 1).
The Central Nervous System (CNS) structures involved in the maintenance of
wakefulness are located in the brainstem, hypothalamus and basal forebrain. The
specific brainstem sites and their neurochemical constituents include the dorsal and
median raphe nuclei (DRN and MRN) [5-HT/serotonin]; locus coeruleus
(LC) [norepinephrine (NE)]; ventral tegmental area (VTA), substantia nigra pars
compacta (SNc), ventral periaqueductal gray matter (vPAG) [dopamine/DA];
laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT)
[acetylcholine/ACh]. The nuclei in the hypothalamus include the tuberomammillary
nucleus (TMN) [histamine/HA] and the posterolateral hypothalamus around the
fornix (LH) [orexin or hypocretin/OX or HCRT]. The basal forebrain wakefulness
Fig. 1 EEG patterns from wakefulness into drowsiness and then into stages 1 through 4 NREM
sleep and into REM sleep. Sleep spindles and K complexes are noted in stage 2 sleep and
saw-tooth waves are seen in REM sleep (adapted from Hauri P. The sleep disorders. Curr Concepts
1982;7; with permission) (Hauri 1982)
centers are located predominantly in the diagonal band, substantia innominata and
median septal area [cholinergic/glutamatergic] (Monti 2013).
Pharmacologic agents that increase CNS dopamine release (e.g., amphetamines,
methylphenidate, modafinil/armodafinil) are some of the most potent
wake-promoting compounds available. These agents can enhance the release of
other neurotransmitters including norepinephrine, however because their effects are

negated in dopamine transporter (DAT) knockout mice, it is likely that dopamine
and its physiologic effects are essential for the maintenance of wakefulness (Wisor
et al. 2001).
DA system neurons involved in sleep/wake physiology are located in the upper
mesencephalon. DA neurons arising in the SNc terminate in the dorsal striatum and
DA neurons arising in the VTA project to multiple areas including the mesolimbic
and mesocortical projections. The SNc and the VTA have additional inputs from
the wake promoting nuclei in the DRN, LC, LDT/PPT, TMN, and the LH as well as
the sleep promoting centers in the pre-optic area [ventrolateral pre-optic area
(VLPO)] and basal forebrain (BFB). Thus there is reciprocal interaction between
wake promoting areas and sleep promoting centers (Moore and Bloom 1978).
The average firing rate of dopamine neurons in the VTA and SNc does not vary
across sleep/wake states (Miller et al. 1983), however, it has been demonstrated that
the VTA dopamine neurons fire more burts during wake and REM sleep resulting in
increased release of dopamine in such areas as nucleus accumbens and prefrontal
cortex (Dahan et al. 2007). VTA neurons are also excited in vitro by orexins,
substance P and Corticotropin releasing hormone (CRH) all which promote arousal
(Korotkova et al. 2003, 2006).
Murine DA neurons in the vPAG/DRN areas show Fos activity during waking
but not during sleep. Lesioning experiments of these neurons by both selective and
non-selective agents resulted in a very robust (>20 %) reduction in 24-h amounts of
wakefulness. In contrast, lesions of the 5-hydroxytryptamine (5-HT) neurons in the
same area did not effect the amounts of sleep and wakefulness. Additionally it was
shown that vPAG neurons project to other parts of the reticular activating system
(RAS) including the BF and midline thalamus and receive input from sleep-active
VLPO neurons (Lu et al. 2006a). It is thus likely that DA neurons paly an essential
role in control of wakefulness but corroborative electrophysiologic studies across
all behavioral states need to be carried out (Brown et al. 2012).
Dopamine, like all neurotransmitters, cause evoked responses via post-synaptic
interaction with their respective receptors. Utilizing molecular cloning, two distinct
groups of DA receptors have been characterized in rats; D1-like (D1 and D5) and
D2-like (D2, D3, D4) receptors. Activation of postsynaptic D1 or D2 receptors
increases wakefulness and reduces SWS and REM sleep. Selective stimulation of
DA D2 autoreceptors or blockade of DA D1 or D2 receptors induces sleep with an
increase in SWS and REM (Monti and Monti 2007). However, because data of
dopamine activity in sleep varies among species it is difficult to extrapolate findings
from a murine model to that of human physiology.
A review of the literature on the effect of dopamine treatments on sleep reveals
that it is a complex subject with conflicting results. In general, DA and sub-thalamic
nucleus deep brain stimulation (STN DBS) usually improve sleep (Amara et al.
2012), however higher doses of dopaminergics, especially levodopa, have been
associated with increase in sleep fragmentation and clinically significant insomnia
(Chahine et al. 2013).
In normal sleep, cholinergic neurons in the brainstem pontine laterodorsal

tegmental (LDT) and the pedunculopontine tegmental nuclei (PPT) increase their
firing rate approximately one minute before the onset of REM sleep (Steriade et al.
1990). The LDT and PPT neurons send fibers via the dorsal pathway, one of the
two discrete (RAS) pathways in the CNS, to the thalamus where they project to the
intralaminar nuclei, thalamic relay nuclei, and reticular nucleus of the thalamus.
This cholinergic input allows flow of information through the thalamus onto the
cortex to promote cortical desynchronization (thalamocortical activation). The fir-
ing rate of the LDT/PPT neurons are sleep state–specific with high-frequency firing
during wakefulness and decreased firing during stages N1–N3 of non-REM
sleep. During REM sleep, their activity abruptly increases (thought to be secondary
to release from monoaminergic inhibition) (Pace-Schott and Hobson 2002; Steriade
1996; Armstrong et al. 1983; Espãna and Scammell 2004, 2011). Mixed popula-
tions of noncholinergic (GABAergic) and cholinergic neurons in the basal forebrain
(magnocellular preoptic nucleus in the substantia innominata, medial septal
nucleus, and the nucleus of the diagonal band of Broca) send projections
throughout the cortex, hippocampus, and amygdala. They have similar firing rates
as the PPT and LDT nuclei, with the highest firing rates during wakefulness and
REM sleep and the lowest during non-REM sleep (Detari et al. 1999).
The second branch of the ascending RAS (R) innervates the hypothalamus via
the ventral route. These neurons are monoaminergic and include the noradrenergic
locus coeruleus (LC), serotoninergic dorsal and median raphe nuclei, dopaminergic
neurons of the ventrolateral periaqueductal gray matter (vlPAG), and the his-
taminergic neurons originating in the tuberomammillary nucleus (Tork 1990;
Koella 1969; Schonrock et al. 1991; Yang and Hatton 1997). These send fibers
back to the basal forebrain, the ventral preoptic area (VPOA), and subsequently the
entire cerebral cortex. These neurons also have state-specific firing rates; they
collectively fire fastest during wakefulness, slow down during non-REM sleep, and
nearly stop firing during REM sleep (Detari et al. 1999; Espana and Scammell
2011). These monoaminergic neurotransmitters are all associated with maintenance
of wakefulness.
The discovery of excitatory sleep/wake neuropeptides,orxin A (OX-A) also
known as hypocretin-1 (Hcrt-1) and orexin-B (OX-B)/hypocretin-2 (Hcrt-2), has
significantly increased our understanding of sleep/wake regulation, especially its
extreme perturbationand narcolepsy (De Lecea et al. 1998; Sakurai et al. 1998;
Methippara et al. 2000; Espãna et al. 2001), and additionally may help explain some
of the non-motor aspects of PD (e.g., the excessive daytime hypersomnolence with
and without “sleep attacks” that frequently accompanies the disease).
Hcrt-1 and Hcrt-2 are produced from the same precursor, preprohypocretin
(ppHcrt), by a small number of cells located in a paired set of nuclei in the lateral
hypothalamus (Kilduff and Peyron 2000). These neurons have diffuse projections
throughout the CNS, including adjacent hypothalamic cell groups, the limbic
system, the periaqueductal gray, dorsal raphe, and the lateral parabrachial nucleus.
The Hcrt neurons receive afferents from GABAergic, glutamatergic, and
cholinergic neurons.
There are two known Orexin/hypocretin receptors (OX1R/HcrtR1and

OX2R/HcrtR2), both of which are excitatory G-protein coupled receptors
(Sakurai et al. 1998) that interact with the two Hcrt (OX) peptides.
The HcrtR1 receptor is exclusively selective for Hcrt1 (OX-A), whereas HcrtR2
has affinity for both Hcrt1 (OX-A) and Hcrt2 (OX-B) (Chemelli et al. 1999).
HcrtR1 and HcrtR2 are differentially distributed in structures regulating sleep and
wake with HcrtR1 exclusively expressed in the LC and Hcrt2R selectively
expressed in the TMN and both receptors co-expressed in the DR (Marcus et al.
2001). This differing specificity supports the hypothesis that the two hypocretin
neuropeptides perform different functions. It appears that Hcrt1 is responsible for
maintenance of sleep and wake episodes, whereas Hcrt2 is involved in the main-
tenance of skeletal muscle tone while awake (Kiyashchenko et al. 2001).
The lateral hypothalamus also contains several distinct cell groups, which
contain neurons that produce neurotransmitters having differing effects on
sleep/wake regulation. As previously discussed, the hypocretin neurons produce
wake-active neuropeptides. In addition, there are neurons that contain
melanin-concentrating hormone (MCH) that are distributed throughout the
postero-lateral hypothalamus in close proximity to the Hcrt neurons; they are active
during sleep, exhibiting slow firing during non-REM sleep,followed by a significant
increase in firing during REM sleep, MCH neurons are silent during wakefulness
(Konadhode et al. 2015). There is also evidence that these neurons actively inhibit
the ascending monoaminergic systems to suppress wakefulness through feedback to
the same monoaminergic cell groups that are activated by the Hcrt neurons
(Torterolo et al. 2011).
Recently, another set of sleep-promoting neurons has been identified within the
lateral hypothalamus that are GABA and galaninergic. GABA and galanin are
inhibitory neurotransmitters that are found in the ventrolateral preoptic area (VLPO)
and the median preoptic area (MnPO), both of which are instrumental in the onset
of sleep (Sherin et al. 1996; Gong et al. 2004). The sleep-active neurons in the
VLPO fire fastest during non-REM sleep, with significant decrease in firing during
REM sleep, and are silent during wakefulness (Szymusiak et al. 1998; Takahashi
et al. 2009; Suntsova et al. 2002). The MnPO neurons begin to discharge just before
non-REM sleep starts and persist during both REM and non-REM sleep (Espana
and Scammell 2011). This has led to the hypothesis that MnPO neurons begin the
process of sleep onset, whereas the VLPO neurons are necessary to maintain sleep
(both non-REM and REM sleep) in conjunction with the MCH neurons. In addi-
tion, sleep maintenance is thought to be promoted by continuous firing of the VLPO
and MnPO neurons along with the GABAergic cells within the lateral hypothala-
mus. They act to further inhibit the arousal system by inhibiting the Hcrt neurons
that are adjacent to the lateral hypothalamus (Hassani et al. 2010) (Fig. 2).
The interaction between the sleep promoting centers and the wake
promoting/maintenance centers is complex with many elements that have not been
fully elucidated or are as yet unknown. Hobson et al. (1975), Saper et al. (2001) have
proposed that there is a mutual inhibitory system on the order of an electrical flip-flop
switch that is able to maintain state stability until such time that an orderly transition
Fig. 2 Anatomy of wakefulness and hypocretin neural groups. a Dorsal and ventral reticular
formations are shown with the dorsal cholinergic system (blue) sending fibers into the thalamus
(green) and basal forebrain. The thalamus then projects out over the cortex by way of the
thalamocortical projections. The ventral aminergic pathway is associated with wakefulness. b The
hypocretin cell group in the lateral and posterior hypothalamus sends excitatory neurons to the
cholinergic and monoaminergic groups of the reticular formation (all awake promoting cell
groups). BF basal forebrain; VTA ventral tegmental area (adapted from Espana RA, Scammell TE).
From: Sleep neurobiology for the clinician. Sleep 2004;27:812; (with permission ) (Espãna and
Scammell 2004)
can occur. This model works for both the sleep/wake “switch” as well as for the
ultradian REM on and REM off “switch”. The result of the interaction of these
“switches” gives rise to orderly sleep state changes (the sum total of which is called
sleep architecture) with its transitions from wakefulness into Non REM sleep and the
appearance of REM sleep on average of every 90 min (Lu et al. 2006b). The
orchestration of the timing of onset and offset of the neural sleep and wakefulness
centers is governed in part by the timing of state specific firing of the neurons in each of
the previously described centers in the brainstem, hypothalamus and basal forebrain
with orexin presumably the master conductor (stabilizer) of this orchestra (Table 1).
Pathophysiology of Parkinson’s disease and its relationship to Sleep/Wake
pathophysiology
The pathophysiologic explanation of the motor symptoms of PD has been well
characterized. It is now established that Lewy bodies (LBs) and Lewy neurites
(LNs), the characteristic intracellular proteinaceous inclusions of a-synuclein
located in the soma and neuronal processes does not start in dopaminergic neurons
within the substantia nigra (SN), but rather starts in the olfactory bulb, anterior
olfactory nucleus and the dorsal motor nucleus of the vagus nerve. Braak has
proposed a six-stage progression of neuropathologic changes leading to the char-
acteristic clinical entity, Parkinson’s disease. Additional work has shown that the
peripheral parasympathetic nervous system is affected in the earliest stages. The
clinical correlates (Stage 1) are olfactory dysfunction and constipation accounting
for some of the initial “pre-motor” non-motor symptoms. Stage 2 describes
pathologic changes at the level of the medullary brainstem and then ascending to
more rostral structures. The SN is affected only in Stage 3, and the first motor
Table 1 State-specific firing rates of brainstem, hypothalamic and cortical neuronal groups
Site Neurotransmitter Wakefulness Non-REM REM
sleep sleep
Basal forebrain Acetylcholine ++++ + ++++
LDT/PPT Acetylcholine ++++ +++!0 ++++
Dorsal and median 5-HT ++++ ++ 0
raphe
Locus coeruleus Norepinephrine ++++ ++ 0
TMN Histamine ++++ + 0
Ventrolateral preoptic GABA/galanin 0 ++++ ++++
area/median preoptic
area
Ventrolateral Dopamine ++++ ++ 0
periaqueductal
gray/lateral pontine
tegmentum
Sublaterodorsal nucleus GABA/glutamate 0 0 ++++
Lateral hypothalamus Melanin-concentrating 0 0 ++++
hormone
Abbreviation GABA, c-aminobutyric acid (Swick 2012)
symptoms are usually noted when the pathologic process has entered Stage 4 by
which time most of the SN has already degenerated (Braak et al. 2003). This
sequence of pathologic changes may explain the earlier onset of many, if not all, of
the non-motor symptoms vis-à-vis the onset of the classic motor findings of PD and
other synucleinopathies (Grinberg et al. 2010) (Fig. 3).
As noted previously, sleep disturbances in PD are numerous and multifactorial.
In broad terms, they can be divided into those disturbances that occur during the
sleeping episode and those that occur during waking hours. The precise control of
the circadian sleep/wake cycle and the ultradian REM/non-REM cycle is still not
fully understood. However, there are generalizations that can be made and that have
solid scientific support.
Studies of sleep architecture in patients with PD have shown inconsistent or
absent abnormalities with the exception of reduced REM sleep atonia (Diederich
et al. 2013). The most consistent findings have been reduced sleep efficiency (SE),
increase in sleep fragmentation, and increased arousals (Tandberg et al. 1998;
Porter et al. 2008).
In a 2014 study (Joy et al. 2014) PSG evaluations were carried out in 30
drug-naïve newly diagnosed PD patients (M:F = 23:7) with a mean duration of
illness of 9.7 ± 9.5 months who were then started on levodopa. The Hoehn&Yahr
(H&Y) stage was 1.8 ± 0.4 and a mean UPDRS motor score at baseline was
27.7 ± 9.2. Disturbed sleep was noted in 18 patients; with difficulty falling asleep
in 12, increase in WASO (wakefulness after sleep onset) in 17 and early morning
awakening in 8. Two exhibited an increase is total sleep time (TST) and 2 had PSG
criteria for RBD. RLS/PLMD symptoms were present in 5. Nocturnal sleep as
Fig. 3 Temporal evolution of a-synuclein pathology could explain the onset of RBD before
parkinsonism and/or dementia. Schematic of brainstem nuclei and connections pertinent to REM
sleep, movement, and cognition. As per the Braak staging scheme, the temporal sequence of
a-synclein pathology begins mainly in the medulla and then ascends to the cortex (6 stages). In
stage 1 (not shown), the dorsal IX/X motor nucleus, intermediate reticular zone and olfactory bulb is
affected, with presumably coexisting degenerative changes in these structures. In stage 2, there is
progression in the structures involved in stage 1, plus the caudal raphe nuclei, MCRF, Peri-LC
structures, and possibly SLD. RBD may evolve when sufficient degenerative changes have occurred
in the SLD, peri-LC structures and MCRF (denoted by red Xs within nuclei). In stage 3, there is
progression in the structures involved in stage 2, plus the PPN, SN, and NBM (denoted by red Xs
within nuclei). When sufficient degeneration occurs in the NBM (denoted by red Xs within nuclei).
When sufficient degeneration occurs in the NBM, then cognitive changes become manifest.
Additional a-synuclein pathology and neurodegeneration evolves in limbic and neocortical
structures over stages 4–6 (not shown)/This temporal sequence of pathology could explain why
RBD precedes Parkinsonism and dementia in many patients with Lewy body pathology. AHC
anterior horn cell, LC locus coeruleus, LDTN laterodorsal tegmental nucleus, LPT lateral pontine
tegmentum, MCRF magnocellular reticular formation, NBM nucleus basalis of Meynert, PC
pre-coeruleus, PPN pedunculopontine nucleus, SLD sublaterodorsal nucleus, SN substantia nigra,
vlPAG ventrolateral part of the periaqueductal grey matter. From Boeve et al. Brain 2007;
130:2770–2788. Reprinted with permission from Oxford University Press (Boeve et al. 2007)
assessed by the Pittsburgh Sleep Quality Index (PSQI) was impaired in 10 (33 %).
The average ESS was 4.0 ± 3.4. PSG data revealed reduction in sleep efficiency
(SE); delay in sleep onset latency (SOL), and increase in stage 2 Non REM (N2)
latencies. There was a “slight” reduction in N2 and N3 (slow wave sleep).
The REM sleep latency was increased to a mean of 166.5 ± 101.7 min. The
average AHI was 8.3 ± 12.1 with an average oxygen saturation of 95.4 ± 2. With
the mean desaturation events/hour = 15.97 ± 20.92. Thirteen of 30 patients had an
elevated AHI (defined as >5 events/hour). The patients had a mean periodic limb
movement (PLM) index of 27.5 ± 49.05, with 17 of 30 having an abnormal PLM
index of >5.
In another study, 23 drug naïve PD patients and 31 age and gender matched
controls were compared using the Parkinson’s Disease Sleep Scale (PDSS) and the
ESS. A PSG was done on both groups of subjects. Of the 23 PD subjects, the 12 that
were started on levodopa were reassessed via scales and PSG. The results demon-
strated that the PD subjects had lower (worse) total PDSS scores than controls with
significantly lower PDSS 3 scores (difficulty in sleep maintenance), PDSS 6 (dis-
tressing nighttime dreams) PDSS 8 (nocturia) PDSS 11 (nocturnal muscle cramps)
PDSS 12 (painful dystonia), PDSS 13 (tremor on awakening) and PDSS 14
(non-refreshing nocturnal sleep). The sleep architecture changes were reduced N3
and R sleep stages and increased SOL and WASO. REM sleep behavior disorder by
history and/or the demonstration of REM sleep without atonia on PSG was found in
22 % of PD patients compared to 0 % in controls. Following 8 weeks of levodopa
therapy the subjects demonstrated improved SE with reduced SOL and WASO
coupled with improved PDSS scores. There was no statistical change in SWS (stage
N3) or REM sleep duration. Parenthetically, there was no change in daytime alert-
ness as noted by absence of any change on ESS (Ferreira et al. 2014).
The specific causes of these abnormalities are multifactorial and direct
clinico-pathological assessments are difficult. Sleep fragmentation has been asso-
ciated with longer disease duration, female gender and depression (Gjerstad et al.
2007). It is generally considered that sleep fragmentation in PD can be primary, i.e.,
the consequence of disrupted sleep architecture or secondary to the nocturnal
occurrence of PD symptoms (tremor, dystonia, rigidity), effect of medications, sleep
disordered breathing, RLS/PLMDs, or nocturia.
Thus far, only one study has tried to correlate pathologic changes in neural
groups with subjective “sleep problems” in PD patients (Kalaitzakis et al. 2013).
There was a statistically significant association between disturbed sleep in PD and
the presence of a-synuclein deposition in the LC (most robust) and the raphe nuclei;
hypothalamic areas including the paramamillary nuclei and posterior nucleus;
subcortical/limbic system including the amygdala, thalamus and entorhinal cortex
regions. In addition, there was a statistically significant increase of tau pathology in
the amygdala, CA2 sector of the hippocampus and entorhinal cortex. Overall, the
more widespread the degree of pathology, the greater the reported sleep problems.
The PPN has also been posited to impact sleep/wake disruption, especially sleep
fragmentation, in PD. It is involved in sleep and REM cycling via cholinergic
ascending thalamic pathways (Monderer and Thorpy 2009). DBS stimulation of the
PPN, which is done to treat severe gait disorders, has been associated with
improvement in subjective sleep and increased REM sleep, (Amara et al. 2011;
Peppe et al. 2012) but specific pathologic confirmation is lacking.
Assessment of Clinical Sleep Disorders in PD
As with most aspects of PD management, obtaining careful history is the most
important diagnostic approach for sleep/wake disorders. It is necessary to carefully
evaluate the sleep patterns and the presence of abnormal movements and/or
behavior and their frequencies during the night. This information should be
obtained from the patient’s bed-partner (if available). Careful note of the number of
awakenings and characterization of the daytime sleepiness e.g., whether the indi-
vidual experiences sudden sleep attacks or excessive drowsiness that interferes with
daytime functioning and whether the individual takes naps (how often and for how
long), need to be ascertained. In addition to obtaining a general medical history it is
important to inquire about all co-morbid conditions that can impact sleep-wake
regulation and perform a thorough review of the medications that the patient is
taking for their PD and any other conditions including over-the-counter drugs.
Polysomnograms are always justified if sleep apnea is considered. They can also
help differentiate PLMS and RBD from mimics, such as epilepsy or night terrors.
Multiple sleep latency tests can help partially quantify excessive daytime sleepiness
but are probably not superior to history unless true narcolepsy is suspected.
2.1 REM Sleep Behavior Disorder (RBD) and Its

Relationship to PD
James Parkinson, in his Essay on the Shaking Palsy published in 1817, noted that
disturbed sleep, in addition to the motor symptoms, significantly affected many of
the patients he studied (Parkinson 1817). He described: “tremulous motion of the
limbs occur during sleep, and augment until they awaken the patient, and frequently
with much agitation and alarm.” In his description of “Case VI,” Parkinson wrote
that the patient’s attendants observed movements during sleep that increased until it
awakened him: “when he always was in a state of agitation and alarm” (Parkinson
1817). This may be the first description of RBD, a condition that has been asso-
ciated with PD; this non-motor symptom can start years, if not decades, before the
development of the classical clinical motor picture.
RBD is defined polysomnographically as the absence of muscle atonia during
REM sleep, demonstrated by sustained muscle activity (tonic activity) in REM
sleep and/or excessive transient muscle activity during REM sleep in the chin or
limb EMG (Berry et al. 2015) (Fig. 4).
This loss of muscle atonia can lead to physical dream enactment with potential
injury to the patient and/or bed partner. The identification of increased muscle
tone/activity on the PSG, in the absence of any behavioral component, is known as
REM sleep without atonia (RWA) (Gagnon et al. 2002). In the absence of any
associated neurological disorder, dream enactment is called idiopathic RBD.
When RBD occurs as a consequence of drugs or accompanies a separate identifiable
neurologic disorder, such as narcolepsy or a neurodegenerative disorder, it is
considered secondary or symptomatic RBD.
It is now accepted that RBD is strongly associated with the development of
synucleinopathies, including PD, multiple systems atrophy (MSA) and Dementia
with Lewy bodies (DLB). The association between RBD and clinically diagnosed
PD was described by Schenck et al. in 1996, where there was a delayed emergence
of parkinsonian symptoms in 38 % of the 29 men who were previously diagnosed
Fig. 4 Polysomnograms showing normal REM sleep epochs and REM sleep without Atonia.
Thirty-second epoch polysomnograms showing normal REM sleep (a) and REM sleep without
atonia-the electrophysiologic substrate for RBD (b). In A, note the absence of electromyographic
(EMG) activity in the submental (Chin 1-Chin 2), and limb (Leg EMG) derivations, whereas
increased EMG tone is present in the submental (Chin 1-Chin 3), upper limb (Left arm-Right
Arm), and lower limb (Left Leg-Right Leg) derivations in B (denoted by red arrows). From Boeve
et al. Brain 2007; 130:2770–2788. Reprinted with permission from Oxford University Press
(Boeve et al. 2007)
with RBD (mean interval, 3.7 years) (Schenck et al. 1996a). Since then, there have
been numerous reports corroborating the association of RBD and PD, with some
individuals developing RBD as long as 50 years before the onset of motor mani-
festations of PD (Claassen et al. 2010). In the longest followed series, 81 % of the
cohort (not lost to follow-up) developed parkinsonism a mean of 14 years after the
onset of RBD (Schenck et al. 2013). Primary RBD is associated with other
pre-motor features of PD including visual changes, olfactory deficits and consti-
pation (Postuma et al. 2006; Iwanami et al. 2010).
The frequency of RBD is between 33 and 60 % in patients with PD (Gagnon
et al. 2002). Within the PD population, RBD correlates with dementia, axial
symptoms (gait) and hallucinations (Pacchetti et al. 2005). It is postulated that the
brainstem degeneration responsible for RBD is also responsible for the intrusions of
dream mentation into wakefulness which are manifested as hallucinations (Comella
et al. 1993; Arnulf et al. 2000; Manni et al. 2002).
The association between RBD and PD is not exclusive. RBD has been associated
with other synucleinopathies:DLB (50–80 % of cases), MSA (80–95 % of cases),
and pure autonomic failure (PAF) (Boeve et al. 2007; Spillantini et al. 1998; Plazzi
et al. 1997) There also have been reports of RBD in patients with suspected pro-
gressive supranuclear palsy (PSP), spinocerebellar atrophy-type 3 (SCA-3), as well
as a case of amyotrophic lateral sclerosis (ALS) and a case of Alzheimer’s disease
(AD) (Arnulf et al. 2005; Friedman 2002; Sforza et al. 1997; Schenck et al. 1996b).
Of note, the non-synucleinopathies (PSP, SCA-3, and AD) usually have the onset
of RBD concurrently or after the onset of motor symptoms of parkinsonism,
whereas RBD typically starts years, if not decades, before the onset of cognitive and
motor symptoms of PD, DLB, MSA and PAF (Boeve et al. 2007).
The pathophysiology of REM without atonia is partially understood. The sub-
laterodorsal nucleus (SLD; also known as the subcoeruleus or peri-LCa), located
ventral to the LC,contains neurons that are both GABAergic and glutamatergic
(Sakai et al. 1979). The cells in the SLD have a subgroup of projections to the
medial medulla and the ventral horn of the spinal cord, and are most active during
REM sleep (Boissard et al. 2002; Verret et al. 2003; Lu et al. 2006b; Xi et al. 2004).
Studies have shown that activation of the SLD region produces atonia and
REM sleep–like EEG activity while inhibition of the SLD promotes wakefulness
and reduces REM sleep (Sakai et al. 1979; Lu et al. 2006b; Hendricks et al. 1982).
Lesions of the SLD suppress REM sleep atonia and reduce REM
sleep. Degeneration of neurons near the SLD has been reported in some patients
with RBD (Boeve et al. 2007). There is also strong evidence that the SLD neurons
are strongly inhibited by REM sleep–suppressing neurons in the midpons (Lu et al.
2006b; Boissard et al. 2003). These GABAergic cells are located in the ventral part
of the periaqueductal gray and extend out into the lateral pontine tegmentum
(vlPAG/LPT) (Boissard et al. 2003). The vlPAG/LPT inhibits the SLD, and the
SLD in turn inhibits the vlPAG, giving rise to the REM-on/REM-off flip-flop switch
(Espãna and Scammell 2011) (Figs. 5 and 6).
In the Braak schema, involvement of the pathologic process in PD affects the
SLD, the magnocellular reticular formation (MCRF), and the peri-LC alpha
structures as early as stage 2 (Braak et al. 2003), prior to involvement of
dopaminergic areas in the midbrain. As noted, these cell structures play a significant
role in not only regulating sleep/wake but also specifically modulating the
REM/non-REM states. During REM sleep, there is generalized loss of muscle tone
in all voluntary muscle with the exception of the diaphragm and the extra-ocular
muscles (teleologically to prevent the acting out of dreams with potential resultant
injury). In REM sleep without atonia there is loss of this protective mechanism.
Lesions of the subcoeruleus or peri-locus coeruleus, MCRF, PPT, and LDT in
cats and the SLD, which is equivalent to the subcoeruleus in rats, produced
behavioral abnormalities consisting of complex motor activity during REM sleep
consistent with the human syndrome of REM sleep without atonia (Boissard et al.
2003; Hendricks et al. 1982). Boeve et al. have proposed that the SLD in humans
with direct projections to the spinal interneurons, is the final common pathway that
normally inhibits skeletal muscle activity in REM sleep. They also propose that the
indirect route can contribute to loss of muscle tone acting through the MCRF.
Lesioning of the SLD results in reduced excitation of the MCRF thereby resulting
in a decrease in the inhibition of spinal motor neurons directly or via spinal
interneurons. It is not known if degeneration of the MCRF is sufficient to cause
RBD in humans (Boeve et al. 2007).
Fig. 5 Proposed nuclei involved in REM sleep control as shown on human brainstem templates.
Letters represent cross-sectional views through the brainstem, with A corresponding to the
pontomesencephalic junction, B to the upper/mid pons, C to lower/mid pons, and D just rostral to
the pontomedullary junction. The REM-off region is represented by the vlPAG and LDT in red,
and the REM-on region is represented by the PC and SLD in green. eVLPO extended part of the
ventrolateral preoptic nucleus, LC locus coeruleus, LDTN laterodorsal tegmental nucleus, LPT
lateral pontine tegmentum, PC pre-coeruleus, PPN pedunculopontine nucleus, RN raphe nucleus,
SLD sublaterodorsal nucleus, vlPAG ventrolateral part of the periaqueductal grey matter. From
Boeve et al. Brain 2007; 130:2770–2788. Reprinted with permission from Oxford University Press
(Boeve et al. 2007)
Pathological examinations of patients with RBD have shown >90 % have Lewy
body pathology (Boeve et al. 2013). Other studies of primary RBD patients without
clinical signs of PD have shown intermediate Lewy body pathology further
strengthening the argument that RBD is associated with, and generally precedes the
onset of clinical synucleinopathies (Iranzo et al. 2010; Miyamoto et al. 2011; Shin
et al. 2013).
It is possible to exhibit the electrophysiologic signature of RBD (i.e., REM sleep
without atonia [RSWA]) on an overnight polysomnography (PSG) but not exhibit
oneiric (dream like) behavior. On the other hand, dream-enactment behavior has
been reported in other conditions, such as untreated obstructive sleep apnea,
sleep-walking and sleep terrors in adults, posttraumatic stress disorder, or as an effect
of alcohol, drugs, or drug withdrawal. Long-term follow-up will be needed to dif-
ferentiate these forms of oneiric behavior from RBD with subsequent development
of degenerative neurologic conditions (Manni et al. 2011). The International
Classification of Sleep Disorders: Diagnostic & Coding Manual e d.2 (ICSD-2) has
stipulated that to diagnose RBD there has to be RSWA on the overnight PSG and
either a history of injurious, potentially injurious, or disruptive behavior or abnormal
sleep behavior during the PSG (American Academy, 2014). It needs to be noted that
Fig. 6 Proposed pathophysiology of REM sleep behavior disorder in humans. Excitatory

projections represented by ⊕, inhibitory projections by (−), with the size of the symbols
representing the relative effect of each projection on the synapsing nuclei. Nuclei are represented
by circles or ovals, with solid colored circles and ovals reflecting those with normal populations of
neurons, and speckled circles and ovals reflecting those with significantly reduced populations of
neurons. An X reflects ablation of a nucleus. The relative tonic influences of each projection are
represented by line thickness, with thicker lines depicting stronger influences, thinner lines
depicting weaker influences, and dashed and dotted lines depicting weak influences due to damage
to neurons in the respective nuclei. The REM-off region is represented by the vlPAG and LPT in
red, and the REM-on region is represented by the PC and SLD in green. The SLD (or analogous
nucleus in humans) projects to spinal interneurons (“direct route,” denoted by dotted line from
SLD to spinal interneurons) and likely represents the final common pathway that causes active
inhibition of skeletal muscle activity in REM sleep. The “indirect route,” denoted by dashed line
from SLD to the MCRF to the spinal interneurons, may also contribute to EMG atonia. However,
in humans, it is not yet known whether lesions in structures which project to and from the MCRF,
and lesioning the MCRF itself, are critical in affecting EMG atonia during REM sleep. EMG
electromyogram, eVLPO extended part of the ventrolateral preoptic nucleus, LC locus coeruleus,
LDTN laterodorsal tegmental nucleus, LPT lateral pontine tegmentum, MCRF magnocellular
reticular formation, PC pre-coeruleus, PPN pedunculopontine nucleus, RN raphe nucleus, SLD
sublaterodorsal nucleus, vlPAG ventrolateral part of the periaqueductal grey matter. From Boeve
et al. Brain 2007; 130:2770–2788. Reprinted with permission from Oxford University Press
(Boeve et al. 2007)
RSWA is not the same as RBD. Even though RSWA may represent a precursor to
the development of clinical RBD, there is insufficient data in patients with RSWA to
convincingly prove progression to the clinical syndrome (Boeve et al. 2007).
However, it is generally assumed that RSWA is the “pathophysiologic” component
of RBD, most truly associated with PD.
An interesting observation concerning the quality of motor behaviors and speech
during the time of the motor/behavioral episodes of patients with RBD and PD has
been reported. Using nocturnal videography during PSG and bed partner
questionnaires, a surprising and significant improvement in the speed, strength, and

fluidity of motor movements was observed or reported along with improvements in
the quality of speech with evidence of improved articulation, loudness, and ability
to be understood during the RBD episode. This phenomenon was also noted in
patients with multiple system atrophy (MSA) during their episodes of RBD, but the
degree of improvement was less (De Cock et al. 2011). It has been posited that
movements during RBD originated in the motor cortex and descended through the
normal pyramidal tracks bypassing the extra-pyramidal system owing to the
brainstem lesions that have disrupted the normal ponto-medullary pathways that
would ordinarily facilitate REM sleep atonia (De Cock et al. 2007).
RBD can cause considerable morbidity to the patient and bed partner and does
sometimes require treatment. Pharmacologic therapy for RBD is largely based on
case reports and series. However, common clinical practice papers have been
published describing the use of clonazepam as the treatment of choice for the
management of idiopathic RBD without PD (Gagnon et al. 2006). Other drugs have
also been reported to decrease the frequency and/or severity of RBD. These include
melatonin, levodopa, pramipexole, carbamazepine, donepezil, galantamine, triazo-
lam, clozapine, and quetiapine (Takeuchi et al. 2001; Tan et al. 1996; Fantini et al.
2003; Bamford 1993; Ringman and Simmons 2000; Boeve et al. 2001, 2003;
Anderson and Shneerson 2009). There are several pharmacologic agents that can
induce or aggravate the symptoms of RBD, including monoamine oxidase inhibi-
tors, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs).
The most common implicated agents are fluoxetine and mirtazapine (Gagnon et al.
2006). A PSG study looking at patients taking SSRIs found an increase in elec-
tromyogram (EMG) activity during tonic submental REM sleep compared with
control subjects (Winkelman and James 2004). Therefore, withdrawal of these
agents could be considered if applicable.
3 Excessive Daytime Sleepiness and PD
Sleepiness is a problem reported by 10–25 % of the population (depends on the

definition used and the population sampled). It is more frequent in young adults and
the elderly. Sleepiness is a physiologic need that expresses itself through the speed
of onset of sleep; the continuity and “depth” of sleep [i.e., how easily sleep is
disrupted] and how long sleep occurs. Excessive daytime sleepiness, defined as
inappropriate and undesirable sleepiness during waking hours (including involun-
tary dozing), is one of the most commonly reported complaints in PD, affecting PD
patients much more than age matched controls. The degree of EDS has been shown
to be a key determinant of these patients’ quality of life (Abbott et al. 2005; Karlsen
et al. 2000; Tandberg et al. 1998, 1999; Barone et al. 2009; Knie et al. 2011). As a
complaint, EDS can be multifactorial, it might be caused by fragmented sleep
resulting from primary sleep disorders such as obstructive sleep apnea, periodic
limb movement disorder, narcolepsy, idiopathic hypersomnia, or behaviorally
induced insufficient nocturnal sleep. Medications, pain syndromes, and numerous

medical and psychiatric disorders also have been associated with significant EDS.
There is also speculation that EDS is a marker for the subsequent development of
PD (Berry et al. 2015; Postuma et al. 2009; Hansen et al. 2013).
The severity of EDS in patients with PD has been shown to increase with older
age, male sex, dopaminergic use, disease severity and disease duration (Ondo et al.
2001; Hobson et al. 2002; Roth et al. 2003). There have been conflicting reports
about the association of Hoehn and Yahr stage and the degree of EDS (Kumar et al.
2003; Lees et al. 1988). It has been suggested that the degree of daytime sleepiness
is related to the brainstem pathology of the PD itself, with direct effects on the
wake/sleep (REM/non-REM–specific brainstem centers) and not on the nocturnal
motor impairment, cognitive deficits (if any), or anti-parkinsonian medications
(Arnulf et al. 2002; Stevens et al. 2004). However, dopaminergic agents have been
implicated in causing sudden-onset sleep episodes (sleep attacks) and EDS in PD
defined as “sudden, irresistible and overwhelming sleepiness that occurs without
warning and is not preceded by being sleepy, as well as increased tendency towards
daytime sleep in general” (Arnulf 2005). It has been speculated that the EDS and
episodes of sudden sleep attacks seen in some patients with PD are similar to that
seen in patients with narcolepsy, a central hypersomnia characterized by severe
EDS and intrusion of REM sleep phenomena during wakefulness (cataplexy, sleep
paralysis, hallucinations, and sleep fragmentation), although data on early onset
REM in PD is mixed (Ondo et al. 2005; Poryazova et al. 2010; Roth et al. 2003;
Hogl et al. 2003).
Narcolepsy with cataplexy is characterized by loss of hypocretin-containing cells
in the lateral hypothalamus. It is thought to be due to an autoimmune process but
other etiologic factors have been reported to be associated with the loss of Hcrt
neurons (Sakurai et al. 1998; De Lecea et al. 1998). The status of hypocretin levels
in patients with PD has been controversial (Fronczek et al. 2008) looked at three
brain compartments to investigate the status of the hypocretin neurons in patients
with PD. They measured Hcrt levels in postmortem ventricular cerebrospinal fluid,
Hcrt concentrations as peptide fragments from the cerebral cortex, and counted the
number of Hcrt neurons in the lateral hypothalamus. They found that Hcrt tissue
concentrations were 40 % lower in PD patients with only a 25 % reduction in
ventricular CSF levels. The reduction in the absolute number of Hcrt neurons was
50 % lower than controls. Typical LB pathology was present in the perifornical
hypothalamus, which established that the PD pathology was active around Hcrt
neurons. Of note, LB inclusions were seen in only a minority of Hcrt neurons in
these patients. This may explain why the reduction in Hcrt levels is not as complete
as that seen in narcolepsy and why the clinical syndromes have overlapping features
such as sleep-onset REM and RBD but no reports of cataplexy (Ebrahim et al.
2003). It has been postulated that patients with narcolepsy without cataplexy may
have a reduced but not an absent number of Hcrt neurons in the hypothalamus.
Thannickal et al. reported that there was an increasing loss of Hcrt cells as PD
progressed and this was accompanied by a concomitant loss of MCH cells
(Thannickal et al. 2007). They rated the loss of cells across all Braak stages. At H&Y
stage I, they found a 23 % loss whereas at H&Y stage 5 there was a 62 % loss. MCH
neural loss was lowest at stage 1at 12 % and highest at stage 5 at 74 %. The losses
were independent of disease duration. They posited that the sleepiness experienced
by patients with PD is due to a combination of loss of Hcrt cells as well as changes
that simultaneously occur in the dopaminergic, adrenergic, and serotonergic neurons
—all of which have wakefulness-producing effects.
Despite pathological Hcrt cell loss, CSF Hcrt levels have not been consistently
lower in PD (Bridoux et al. 2013; Wienecke et al. 2012; Compta et al. 2009;
Overeem et al. 2002).
In 1999, Frucht and colleagues reported on eight patients with PD who had
abrupt onset of sleep episodes (Frucht et al. 1999). The “sleep attacks” occurred
while the patients were driving and had taken either pramipexole (8 patients) or
ropinirole (1 patient). Five of the eight had no warning (i.e., no prodromal
sleepiness) and all episodes ceased with the withdrawal of the medications. Since
the publication of this observation, there were numerous reports of other patients on
all dopaminergic agents including pergolide, bromocriptine, carbergoline, apo-
morphine, lisuride, piribedil, levodopa, tolcapone, and entacapone, who reported
similar experiences (Hauser et al. 2000; Ryan et al. 2000; Ferreira et al. 2000;
Schapira 2000).
In 2001, Ondo et al. looked at 320 consecutive patients charts from a large
tertiary care movement disorder clinic over a three month time frame (17 charts
were eliminated) and found that the average ESS score was 11 (scores >10 are
considered to be consistent with excessive sleepiness) and further analysis found
that sleepiness correlated with longer duration of PD, male sex and use of any DA
agent (Ondo et al. 2001).
In 2002, Hobson et al. reported on the results of the Canadian Movement
Disorders group survey of 638 “consecutive highly functional PD patients without
dementia” to determine the frequency of and predictors for sudden-onset sleep, with
particular emphasis on sleep attacks while driving (Hobson et al. 2002). Utilizing
the Epworth Sleepiness Scale (ESS) and a scale designed for this particular study
(the Inappropriate Sleep Composite Score), they found that EDS was present in
51 % of the respondents. There was no significant difference in ESS scores for any
of the dopaminergic agents that were used in terms of either composite scores or in
the risk of falling asleep while driving. Sixteen patients (3.8 %) had experienced at
least one episode of sudden sleep onset (without warning) while driving. An ESS
score of 7 or higher (scores of 10 or more are considered indicative of a greater
propensity to fall asleep) was the greatest predictor of episodes of falling asleep
behind the wheel. The conclusion of the study was that EDS is common in patients
with PD who are independent and do not have dementia, but they felt that the
sudden onset of sleep attacks was relatively uncommon.
Because of the limitations of survey results, Kaynak et al. studied 15 previously
untreated patients with PSG/MSLT (Multiple Sleep Latency Testing) before and
during treatment with a dopaminergic agent (DA). Before the initiation of DA
therapy, there was no subjective evidence of daytime sleepiness. The researchers
found that UPDRS subset III scores were significantly improved with DA
treatment; however, subjective daytime sleepiness increased as measured by an

increase in ESS scores. In terms of objective PSG findings, there was a trend
towards an increase in total sleep time (TST), sleep efficiency (SE), REM latency
and a decrease in time in bed (TIB) and wakefulness after sleep onset (WASO).
These differences did not reach statistical significance. However, mean sleep onset
latency on the multiple sleep latency test (MSLT) showed significantly shorter sleep
onsets after treatment (8.1 ± 4.7 min; range 7–19) versus values obtained prior to
treatment (13.6 ± 4 min; range 1–16). An MSLT score of <8 min, indicative of
pathologic hypersomnolence, was reported by only one person before treatment but
were obtained in seven patients (47 %) after treatment (Kaynak et al. 2005).
A 2014 study (De Cock et al. 2014) investigated patients with PD (N = 134 of
whom 72 % were male with a mean age of 66) with daytime sleepiness. The
subjects were evaluated with both subjective and objective instruments. The
researchers found that the high frequency of self-reported EDS using the Epworth
Sleepiness Scale (ESS) was in-fact not confirmed by the MSLT. However, an
elevated BMI, a pain complaint or higher sleep disordered breathing (based on
polysomnography) scores were associated with elevated ESS scores and shortened
SOL on the MSLT. The important negative correlations included measures of motor
disability, disease onset, medication (type and dose), depression, insomnia, restless
legs syndrome, REM sleep behavior disorder and nighttime sleep variables (TST,
sleep efficiency, SOL, SWS%, REM sleep%, PLMS, and arousals). Of particular
note was that there was overall poor correlation between ESS and the MSLT, an
observation that has been made several times before (Arand et al. 2005; Ruoff et al.
2015; Trotti et al. 2013). It should be noted that the majority of studies have failed
to show an association between clinically significant sleep disordered breathing and
PD.
In 2015, Tholfsen et al. reported on the development of EDS using the ESS in
early PD patients. Their group found that EDS was more frequent in PD patients
(N = 153), even before treatment initiation compared with control participants
(N = 169), and increased with disease progression over their five-year study period.
They went on to opine that the main risk factor for developing problematic EDS
with time was the presence of early EDS (Tholfsen et al. 2015).
There has been recent evidence that EDS and to some extent nocturnal sleep
problems are related to blunting of the circadian rhythms of melatonin secretion in
patients with PD (Videnovic et al. 2014). There have been reports, using actigraphy,
which show that PD patients have decreased activity levels when out of bed and
increased levels while in bed. Circadian rest/activity rhythm in PD patients was also
noted to decrease with disease severity (Niwa et al. 2011).
Data on circadian melatonin levels in PD is mixed but a recent trial showed
reduced melatonin in general and a marked attenuation of the nighttime melatonin
surge, strongly suggesting a blunting of normal circadian wake/sleep cycling
(Videnovic and Golombek 2013).
The molecular basis of circadian function is well known. The
transcriptional-translational feedback loops are centered in the suprachiasmatic
nucleus (SCN). The average human circadian rhythm is approximately 24.2 h
although individual SCN cells have periods that vary from 23 to 28 h. The strongest
circadian entrainment signal comes from light stimulation of the melanopsin con-
taining retinal ganglion cells via the retino-hypothalamic tract directly into the
hypothalamus/SCN.
Dopamine and CLOCK genes, which regulate circadian control on the cellular
level, have a complex interaction. Dopamine production through tyrosine hydrox-
ylase gene activation (the rate limiting step in DA production) is controlled by
CLOCK genes (Yujnovsky et al. 2006). It is notable that D2/D3 agonists inhibit
mCLOCK and mPer1 gene expression, whereas D1 agonist stimulates these genes
(Imbesi et al. 2009). Of particular importance are studies that have demonstrated
that PD patients have a decrease in the expression of Bmal1 gene during the night,
further suggesting a blunted CLOCK system (Cai et al. 2010).
The treatment of insomnia in PD is remarkably unstudied. Generally sleep
hygiene principles apply. Awakening from wearing off (rigidity, tremor, etc.) can
sometimes benefit from more aggressive nocturnal dopaminergic dosing. Nocturia
is very common in PD and might improve with bladder relaxants and standard
strategies (reduced PM fluid/caffeine/alcohol intake).
The use of melatonin in PD patients with sleep maintenance difficulties has been
shown to be effective in terms of improving subjective assessments of sleep
quantity and daytime sleepiness (5 mg of pharmaceutical grade melatonin)
(Dowling et al. 2005). The use of short acting hypnotics such as the
non-benzodiazepine agonists (zolpidem, eszopiclone, and zaleplon) are often used
but carry risks of psychomotor impairment during the night if the patient awakens
and ambulates. The association of these non-benzodiazepines with confusional
arousals/automatisms also needs to be considered (Abe et al. 2005; Poceta 2011).
Quetiapine and clozapine, used to treat hallucinations, seem to improve sleep in
many patients (Miyasaki et al. 2006).
Several treatments for EDS have undergone controlled trials, but often with
mixed results. First, one needs to try to reduce any medications that are sedating if
possible. If they are taking dopamine agonists (DA) and experience EDS, they
should be warned not to drive or engage in hazardous activities. Down-titration or
discontinuation (if tolerated) of a DA often helps (Razmy et al. 2004). Improved
nocturnal sleep might help EDS in some cases.
In some patients, the addition of a psychostimulant during the day is recom-
mended. Modafinil, a medication that is FDA approved for the EDS of narcolepsy and
sleepiness associated with OSA and shift work sleep disorder has been demonstrated
to be well tolerated in PD patients but its alerting effect is modest (<33 % of patients
responded) (Ondo et al. 2005; Adler et al. 2003; Hogl et al. 2002). In a small trial,
nocturnally administered sodium oxybate, a drug that is used to treat both EDS and
cataplexy in narcoleptic patients, increased slow-wave sleep as a percentage of total
sleep time, and improved subjective nighttime and daytime sleep complaints in
patients with PD (Ondo et al. 2008). In one controlled trial, caffeine did not improve
EDS, but did improve some motor features of PD (Postuma et al. 2012).
Other Associated Sleep Disturbances with PD
3.1 Restless Legs Syndrome and Periodic Limb Movements
Restless legs syndrome (RLS) is a common neurologic disorder that affects 4–10 %
of the general population (Ohayon and Roth 2002). The clinical manifestations
include uncomfortable or unpleasant sensations in the limbs (usually legs) that
begin or worsen during periods of inactivity, are transiently relieved by movement,
and worsen during the evening or night (Allen et al. 2003). RLS closely resembles
akathisia, also reported in PD, but differs in that the urge to move is isolated in the
limbs as opposed to the entire body, the urge to move is relieved with movement far
more successively than with akathisia, and RLS exhibits greater symptom at night
with near complete resolution of symptoms in the morning (Ondo 2014). In many,
but not all patients there is an accompanying motor component of periodic limb
movements (PLMs) that usually occur in sleep but can also occur during wake-
fulness (PLMW) (Pelletier et al. 1992). PLMS may occur in association with RLS
or independently. The robust efficacy of dopaminergic agents for the treatment of
RLS has been considered to support a relationship between RLS and PD.
The main pathology of idiopathic RLS is reduced CNS iron stores. CSF ferritin
is lower in RLS cases, MRI imaging and transcranial ultrasound show reduced iron
stores in the striatum, and Substantia Nigra and pathological studies show reduced
CNS iron staining. Earley et al. has proposed that low cellular iron alters one or
more of the dopaminergic synaptic dynamics (changes in postsynaptic receptors,
presynaptic receptors, synthesis and release or uptake of DA) but the exact rela-
tionship between observed pathology and a dopa-response symptomatology is
poorly understood (Earley et al. 2014).
There have been numerous cross-sectional studies examining the frequency of
RLS symptoms in patients with PD. The generally accepted frequency of RLS in
the PD population is 10–24 %, as reported in many studies of general PD popu-
lations (mostly treated). In a 2011 study, Gjerstad et al. looked at 200 patients with
early untreated PD and compared them to an appropriate community based sample
of controls (Gjerstad et al. 2011). They were unable to find a statistically significant
association between RLS in patients with PD versus controls. They found that the
patients with PD complained of leg motor restlessness (LMR) but did not have the
“urge to move” that characterizes the sensory phenomenon in patients with RLS.
Arnulf in an editorial accompanying the Gjerstad article wondered if the LMR
represents a forme fruste of RLS or is an unrelated phenomenon (Arnulf and
Morgan 2011). In fact, there is some evidence that idiopathic RLS may “protect”
against the subsequent development of PD (Dragan et al. 2015).
Idiopathic RLS is often treated with DA, however within the context of PD
patients who are already on DA, treatment with agents such as gabapentin
enacarbil, or opiates have also been used (Yaltho and Ondo 2010). There are no
controlled trials. It should be noted that caffeine, alcohol, central acting antihis-
tamines, dopamine antagonists, tricyclic antidepressants and serotoninergic reup-
take inhibitors can exacerbate RLS (Ekbom and Ulfberg 2009).
3.2 Sleep Disordered Breathing
The reported frequency of sleep disordered breathing (SDB), usually obstructive

sleep apnea (OSA), in PD has been previously reported to be elevated in patients with
PD but in more recent studies the association has been greatly questioned (Arnulf
et al. 2002; Maria et al. 2003; Diederich et al. 2005). Obesity, the major risk factor for
SDB is relatively uncommon in PD. Therefore, SDB in PD may result from decreased
upper airway muscle tone because of degeneration of the brainstem serotoninergic
neurons that innervate the muscles of the upper airway, deficient respiratory muscle
coordination, or autonomic dysregulation (Kish 2003; Kerenyi et al. 2003; Albin et al.
2008; Kish et al. 2008; Schiermeier et al. 2001; Micieli et al. 2003).
Trotti and Bliwise looked at 55 idiopathic PD patients (mean age 63.9 years)
from a large University Sleep Center who underwent three consecutive night
polysomnograms on their usual DA medications. They were unable to find any
increased risk of obstructive sleep apnea in these patients with specific attention to
apnea-hypopnea index (AHI) when compared to published normative,
population-based data from the Sleep Heart Health Study. Epworth Sleepiness
Scale (ESS) scores, BMI and snoring did not correlate with AHI (Trotti and Bliwise
2010; Nieto et al. 2000).
In a large longitudinal study using data from the Taiwan Longitudinal Health
Insurance Database 2000, 1532 patients were selected with OSA as the study cohort
and 7660 patients were selected as the comparison cohort. Each subject was fol-
lowed for a 5-year period to identify those in whom Parkinson’s disease developed.
Of the 9192 total patients, PD developed in 0.73 % during the 5-year follow-up:
1.24 % of the OSA patients and 0.63 % of the control cohorts. The hazard ratio
(HR) of developing PD during the 5-year follow-up period for OSA was 2.26
(95 % confidence interval [CI] = 1.32–3.88) compared with the control cohort. Of
note, there was no significantly increased HR for the development of PD for male
patients with OSA compared to those without OSA. The HR for women on the
other hand was 3.54 (95 % CI = 1.50–8.34) for patients with OSA compared to
patients without OSA. The authors hypothesized that the reason that women had a
higher HR was that they were more likely to go undiagnosed for longer periods of
time and ultimately had higher number of apneas and greater degrees of hypoxemia
with a higher age at entry into the database. This, along with the observation that
age was a strong factor leading to increasing disease severity accounted for the
greater number of women who developed PD (Sheu et al. 2015;
Szewczyk-Krolikowski et al. 2014).
Cochen De Cock et al. looked at 50 unselected consecutive PD patients, 50
patients diagnosed with PD and a complaint of excessive daytime sleepiness
selected from a group of 115 patients referred for symptoms of EDS, and 50 age-,
sex- and BMI- matched in-hospital controls with no neurological disease and no
sleep complaint. All subjects underwent full medical and neurologic evaluations,
evaluations for depression, ESS, UPDRS part III, MMSE, and an over-night PSG.
They found that sleep apnea (defined as an apnea-hypopnea index of >5) was less
frequent in the PD group (27 % patients, including 6 % mild; 11 % moderate and

10 % severe sleep apnea) than the control group (40 % in-hospital controls,
p < 0.002) Sleep apnea was not associated with increased sleepiness, nocturia,
depression, cognitive impairment and cardiovascular events in patients with PD.
Sleep apnea was more frequent and severe in the most disabled patients. In patients
with REM sleep behavior disorder, snoring and obstructive sleep apnea occurred
more frequently during REM sleep, although chin muscle tone was preserved. Their
conclusion was that obstructive sleep apnea was not a clinically relevant issue in PD
(Cochen De Cock et al. 2010).
Overall, the data for the association of PD and OSA is conflicting and needs
further study. Nasal CPAP (continuous positive airway pressure) is the
“gold-standard” for the treatment of obstructive sleep apnea, although there have
been no large trials confirming its efficacy in PD specifically. Generally, treatment
should be started on patients with an apnea/hypopnea index of 15 or more per hour
of sleep as determined during overnight polysomnography (Maria et al. 2003).
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Regulation and Modulation
of Depression-Related Behaviours: Role
of Dopaminergic Neurons
Basma Radwan, He Liu and Dipesh Chaudhury
Abstract Dopamine, a neurotransmitter produced in various brain regions, is

implicated in regulation of motor control, reward, mood and addiction. Depression
is a serious disorder affecting the day-to-day activities of patients that also imposes
a substantial financial burden on society. The following chapter offers an expansive
demonstration of the heterogeneous dopamine system in the brain, by describing
some of the advances made in unraveling the various dopaminergic neural path-
ways and molecular mechanisms involved in depression. It also sheds some light on
how these same neural pathways might be responsible for the disturbances in sleep
and circadian rhythms experienced by patients suffering from depression.

Keywords Dopamine Depression VTA Sleep Circadian Serotonin Clock

genes LHb LH PPTg/LDTg MSN NAc Chronic social defeat Learned

helplessness D1 and D2 neurons Orexin
1 Introduction
Major depressive disorder (MDD), a heritable complex neuropsychiatric syndrome

characterized by subtle cellular and molecular changes across numerous neural
circuits, occurs across the entire age spectrum (Krishnan et al. 2007; Krishnan and
Nestler 2011; Hyde et al. 2005). The symptoms of depression are heterogeneous
and exist in various subtypes such as atypical, melancholic and psychotic depres-
sion (Krishnan and Nestler 2011; Rush 2007). However, the underlying patho-
physiological changes associated with the various subtypes of depression are still
unsolved. Current treatments for depression, based predominantly on the mono-
amine hypothesis, have low remission rates of 30–40 % (Krishnan and Nestler
B. Radwan H. Liu D. Chaudhury (&)

Division of Science, New York University Abu Dhabi (NYUAD), Experimental Research
Building, Room 106, Saadiyat Island, PO Box 129 188, Abu Dhabi, United Arab Emirates
e-mail: dc151@nyu.edu

DOI 10.1007/978-3-319-46437-4_8
148 B. Radwan et al.
2011; Rapaport et al. 2003; Trivedi et al. 2011). Furthermore, for those patients that
respond to treatment, alleviation of symptoms can take weeks or months to occur.
An understanding of the biological mechanisms of the various forms of depression
is critical, because it is predicted by the World Health Organization (WHO) to be a
leading contributor to the global burden of disease (GBD).
Mood disorders involve deficits in reward processing and motivation, where per-
ception of reward is blunted with a corresponding reduction in motivation to pursue
hedonic goals. Dopamine (DA) signaling in several brain regions has been implicated
in movement control and in modulating reward, behavioural, and motivational pro-
cesses such as emotional and contextual memory, decision-making, approach beha-
viour, and learning (Grace et al. 2007; Schultz 2013). Consequently, dopamine
receptors have been the target for designing clinical therapeutics for various movement
disorders and mental illnesses such as Parkinson’s and Huntington’s disease, and
Schizophrenia. Moreover, antagonists of dopamine receptors attenuate addiction
symptoms (Gong et al. 2016; Yue et al. 2012; Wang and Mantsch 2012). Recent
investigations into mapping the organization of the dopamine system in the brain led
to the conclusion that the dopamine system is diverse in terms of the neurochemical
structure and the distinct circuits made up of subpopulation of DA neurons with
different functions (Lammel et al. 2012).
The DA-producing neurons are mainly located in three regions: the retrorubral
field, the substantia nigra pars compacta (SNC) and the ventral tegmental area
(VTA) (Dunlop and Nemeroff 2007). Dopamine signaling in the reward pathways
in VTA has been implicated in regulating mood. The VTA is made up of
dopaminergic cells (*70 %), GABAergic cells (*30 %) and Glutamatergic cells
(*2–3 %) (Lammel et al. 2011; Ungless and Grace 2012). There are two dopamine
modes of signaling: phasic signaling due to the burst firing of DA neurons in VTA
in response to salient stimuli and tonic signaling due to the slow activity of
VTA DA neurons (Dunlop and Nemeroff 2007). There are three types of physio-
logical responses to reward identified in VTA neurons: type I DA neurons
(*52 %) show phasic responses to reward, type II DA neurons (*31 %) show
sustained excitation to the reward-predicting conditioned stimulus (CS), while type
III DA neurons show sustained inhibition to CS (Cohen et al. 2012). In general, the
in vitro characteristics of dopamine neurons consist of: broad action potential
waveforms lasting on average around 3–10 ms, slow firing rate (1–10 Hz), high
frequency activity or bursting. A subset of DA neurons exhibit a
hyperpolarization-activated inward current (Ih) mediated by G protein-gated
inwardly rectifying K+ channel (Ungless and Grace 2012). Observations that the
in vivo burst firing properties are absent in brain slice preparations suggest that
bursting activity is either induced or regulated by various projections to VTA
(Grace and Onn 1989). The DA neurons in the VTA are heterogeneous in their
electrophysiological profile such that some VTA dopamine neurons do not respond
to dopamine bath application and some have very small Ih currents (Lammel et al.
2008). Furthermore, DA neurons projecting to medial prefrontal cortex (mPFC) and
to nucleus accumbens (NAc) medial shell lack a prominent Ih current (Lammel
et al. 2011). The VTA projections to lateral habenula (LHb) express tyrosine
Regulation and Modulation of Depression-Related Behaviours … 149
hydroxylase (TH) but release gamma-aminobutyric acid (GABA). Additionally,

VTA-LHb cells lack Ih currents similar to VTA-mPFC projection cells and do
exhibit significantly higher firing rate (Stamatakis et al. 2013). The heterogeneous
DA neurons in VTA exhibit differential anatomical distribution such that DA
neurons with distinct electrophysiological properties are believed to be located
within distinctly anatomical subregions within the VTA. Most ‘conventional’ DA
neurons are located in the dorsal and lateral portions of the VTA (Lammel et al.
2011, 2012). Therefore, the functions of the ‘conventional’ DA neurons may not be
applicable to other ‘non-conventional’ DA neurons in other subregions of the VTA,
which might have been largely ignored in previous studies. It is believed that the
distinct locations of the DA neurons might underlie the distinct responses of the
VTA neurons to different aversive and reward stimuli, leading to a functional
heterogeneity as well (Holly and Miczek 2016).
DA neurons in the VTA are also classified into five subcategories based on their
heterogeneous neurochemical structure depending on the existence of the following
proteins: (AADC) which is involved in the synthesis of DA, Vesicular Monoamine
Transporter 2 (VMAT2) and dopamine transporter (DAT) involved in the transport
of Dopamine, D2 autoreceptor (D2R) involved in the autoregulation of dopamine
and vesicular glutamate transporter 2 (VGluT2) involved in the transport of glu-
tamate. “Conventional” dopamine neurons have high expression of VMAT2, DAT
and D2 autoreceptors and lack VGluT2. They are found mostly in the lateral part of
the VTA. Moving medially, DA neurons containing VGluT2 are more frequently
encountered as well as those lacking D2R. In other words, there is a latero-medial
increasing gradient concentration of dopamine neurons that lack the capability of
dopamine transport and autoregulation (Li et al. 2013).
Additionally, the Dopamine receptors are divided into five distinct types, D1-D5,
which are further subdivided into 2 groups, the dopamine 1, including D1 and D5
subtypes and the dopamine 2, including D2, D3 and D4 subtypes (Dunlop and
Nemeroff 2007). The subtypes of Dopamine receptors have different pharmaco-
logical selectivity and involvement in various mental illnesses (Seeman and Van
Tol 1994). In the ventral striatum, the identity of the receptors, either D1 or D2,
segregate the medium spiny neurons (MSN) into two distinct pathways in the dorsal
striatum (Smith et al. 2013). D1-MSNs project to the substantia nigra (SN) and
internal globus pallidus (Li et al. 2015) and constitute the direct pathway, while
D2-MSNs projections to external globus pallidus (GPe) constitute the indirect
pathway, whereby the direct D1 pathway facilitates locomotion and D2 indirect
pathway attenuates movement. Thus, these two pathways have opposing but bal-
ancing roles in regulating motor behaviour.
Further investigation into the organization of the DA system in the midbrain
reveals that DA midbrain neurons in the VTA project to different regions such as
the medial prefrontal cortex (mesocortical), basolateral amygdala (Blaze and Roth
2013) (mesoamygdaloid), the nucleus accumbens core (mesolimbic) and NAc
medial shell (mesolimbic medial shell) (Chaudhury et al. 2013). The mesolimbic
lateral shell pathway consists of DA neurons projecting to the NAc lateral shell that
are scattered throughout the parabrachial nucleus (PBP) in the lateral portion of the
VTA and the medial parts of the substantia nigra (Smith et al. 2013). DA neurons
with different projections form distinct subcircuits in the VTA as they receive
different inputs which likely leads to different functional roles in regulating beha-
viours (Polter and Kauer 2014).
Moreover, the experience-dependent modulation of the excitatory synapses of a
subpopulation of midbrain DA neurons are distinctly modified, after either an aversive
experience versus a rewarding cocaine experience, based on their projections to dif-
ferent target areas, where the change in the synaptic strength in the VTA was mea-
sured by the change in the amino-hydroxy-methyl-isoxazolepropionic acid receptor/N-
Methyl-D-aspartate receptor (AMPAR/NMDAR) ratio (Kauer and Malenka 2007).
For example, the synapses of DA neurons projecting to mPFC and NAc medial shell
were only modified during the aversive stimulus, whereas the synapses on DA cells
projecting to NAc lateral shell were modified by both the aversive and the rewarding
stimuli. Such findings suggest the encoding of the motivational stimulus and its
valence in the DA circuitry occur through parallel processing analogous to the
encoding of sensory stimuli in the sensory systems (Lammel et al. 2011). Such
heterogeneity of the dopamine system might explain the difference in the patho-
physiology associated with the various models depression as will be discussed in the
subsequent sections of this chapter.
2 Dopamine and Behavioural Regulation
High frequency dopamine neuronal activity and the resulting transients in dopamine
release are thought to comprise key learning signals in the brain (Schultz 2007;
Robinson and Wightman 2007) encoding information related to external rewards
and cues with resultant appetitive motivational behaviours. Dopamine transients
occur spontaneously in several brain regions and are most prominent at the pre-
sentation of unexpected stimuli (Robinson and Wightman 2007; Rebec et al. 1997),
rewards (Roitman et al. 2008) and social interaction considered as a rewarding
stimulus for social animals (Robinson et al. 2001, 2002). Social interaction is a
complex behaviour essential for stable social dynamics and ultimately survival in
many species. Impaired social interactions are a hallmark of several psychiatric
disorders including autism, schizophrenia, depression and social anxiety disorders.
In addition to congenital causes of impaired social interaction, external social stress
in humans and animals is considered a major risk factor in the onset and devel-
opment of neuropsychiatric disorders such as depression (Charney et al. 2004;
El-Sayed et al. 2015; Henriques-Alves and Queiroz 2015). The possible rewarding
effect of social interaction is demonstrated by the observed transient DA release that
has been measured directly in the NAc of rats exposed to novel rats using fast-scan
cyclic voltammetry (Robinson et al. 2011). More recent detailed analysis found that
DA signaling in VTA projections to the NAc modulated social behaviour
(Gunaydin et al. 2014). By using novel fiberphotometry techniques, this study

directly measured increased VTA-NAc DA cell activity during social interaction
that was specifically dependent on D1-receptor activation in the NAc (Gunaydin
et al. 2014). In light of the importance of DA signaling in modulating motivational
behaviours such as social interaction, understanding the effect of stressful social
encounters on DA signaling in the brain circuits may be a useful tool in under-
standing DA neural circuit disorders associated with depression. Thus, in order to
understand some of the cellular and molecular mechanisms related to the devel-
opment of depression, the chronic social defeat stress (CSD) based on the
resident-intruder paradigm has been one of the commonly used rodent models of
depression.
At present, the pathophysiology of the depression is unclear. However, recent
approaches combining animal models of depression together with electrophysio-
logical, optogenetic and molecular analysis have begun to reveal a complex
interplay between various neural circuits and cell types in encoding for depression
(Lammel et al. 2014b; Schultz 2007; Robinson et al. 2011; Francis et al. 2015;
Russo and Nestler 2013; Tye et al. 2013, 2011). The afore-mentioned mesolimbic
dopaminergic pathway composed of dopaminergic (DA) neurons in the ventral
tegmental area (VTA) and their projections to the nucleus accumbens (NAc) is
crucial for the recognition of emotionally salient stimuli such as reward (Koob
2008) and aversion (Wenzel et al. 2015). In addition, DA neurons of the VTA-NAc
circuit play a key role in modulating depression-related behaviours (Krishnan et al.
2007; Chaudhury et al. 2013; Tye et al. 2013; Nestler et al. 2002; Berton and
Nestler 2006; Berton et al. 2006; Cao et al. 2010; Friedman et al. 2014). Earlier
work has shown that the in vitro firing rate and in vivo phasic firing events of
VTA DA neurons in the brain reward system is significantly increased in mice
exhibiting the susceptible (depressed) phenotype following exposure to the chronic
social defeat paradigm (Krishnan et al. 2007; Cao et al. 2010; Anstrom et al. 2009;
Razzoli et al. 2011). Conversely, in vivo recordings of rats susceptible to the
learned helplessness paradigm exhibited decreased VTA DA neuron activity and
that the antidepressant ketamine both rescued those rats previously susceptible to
the learned helplessness paradigm and increased VTA DA activity (Belujon and
Grace 2014). Two recent optogenetic studies directly demonstrated the role of
VTA DA neurons in depression (Chaudhury et al. 2013; Tye et al. 2013). In one
study, optogenetic induction of phasic, but not tonic, firing of VTA DA neurons
was shown to rapidly induce the susceptible (depressed) phenotype in mice that had
previously undergone a weak subthreshold social defeat stress paradigm
(Chaudhury et al. 2013). Conversely, the second study showed the opposite effects
where phasic activity of VTA DA neurons rescued stress-induced depressive-like
behaviour in mice that had undergone chronic mild stress (Tye et al. 2013). The
discrepancy between the two studies has been discussed (Lammel et al. 2014b;
Marton et al. 2015) and may highlight differential coding processes of VTA DA
neurons for strong or weak stressful stimuli (Lammel et al. 2014a; Walsh and Han
2014b), which is highly consistent with the fine context-detecting functions of
VTA DA neurons (Walsh et al. 2014a). It has recently been shown that rats put
through a strong stressful paradigm (restrained stress) exhibited increased firing in

the VTA while those through a weaker stress paradigm (mild inescapable stress)
exhibited decreased activity (Valenti et al. 2012). Detailed circuit analysis reveals
that nuclei within the brain may receive differential inputs that result in subtle
differential roles of these subcircuits in encoding for aspects of behaviours (Walsh
and Han 2014b). Thus, a possible explanation for the differential coding for weak or
strong stressors might lie in the existence of functionally distinct populations of
VTA DA neurons. Those VTA DA neurons that exhibited decreased firing fol-
lowing weak stress exposure were located primarily in the medial and central
portions of the VTA (Valenti et al. 2012). Furthermore, VTA DA neurons located
in ventral VTA are excited by noxious footshock while dorsal VTA DA neural
activity is inhibited (Brischoux et al. 2009). Differential activity coding has also
been demonstrated in mice exposed to the same stressor. VTA neurons projecting to
the NAc (VTA-NAc) exhibit increased firing while those projecting to mPFC
(VTA-mPFC) exhibit decreased firing in mice susceptible to social defeat stress
(Chaudhury et al. 2013). Likewise, rapid induction of the depressed phenotype was
observed by (1) optical induction of phasic activity in the VTA-NAc circuit and
(2) optical inhibition of the VTA-mPFC circuit (Chaudhury et al. 2013). These
projection specific DA neurons exhibit differing physiological properties. DA
neurons projecting to NAc exhibit robust Ih currents (hyperpolarization-activated
non-selective cation channel mediated currents) while DA neurons projecting to
mPFC lack robust Ih currents (Friedman et al. 2014; Lammel et al. 2011). The
degree of complexity of these circuits is due to the fact that subpopulations of
VTA DA neurons receive synaptic inputs from different nuclei in the brain. There
are two major excitatory inputs to VTA coming from the laterodorsal
tegmentum/pedunculopontine tegmentum (LDTg/PPTg) and the lateral habenula
(LHb) (Lammel et al. 2012). The LHb, a nucleus that integrates signaling from the
basal frontal cortical areas and midbrain monoaminergic nuclei, has a functional
role in motivated behaviours (Lecca et al. 2014) and LHb neurons projecting
specifically to the rostromedial tegmental nucleus (RMTg), or the tail of the ventral
tegmental area (tVTA), mediate behavioural avoidance (Stamatakis et al. 2012).
Furthermore, the LHb is a key neuroanatomical regulator of midbrain reward cir-
cuits and increased activity of LHb projections to VTA is known to encode for
depression, as studies have shown increased activity of LHb neurons projecting to
the VTA in mice exhibiting the depressed-phenotype following exposure to a
learned helplessness model of depression (Li et al. 2011) and to a chronic social
defeat stress paradigm (Chaudhury et al. 2014).
It is likely therefore that aberration in the VTA-LHb-VTA loop may lead to
depression-like behaviours. Neurons from the LDTg synapse primarily on VTA DA
neurons projecting to the NAc while neurons from the LHb synapse either unto
VTA DA neurons projecting to the mPFC or unto GABAergic neurons in
the RMTg (Lammel et al. 2012). In addition, these circuits encode opposing
behaviours as selective activation of LTD and LHb inputs to the VTA elicit reward
and aversive behaviours respectively (Lammel et al. 2012), while LHb neurons
projecting specifically to the RMTg mediate behavioural avoidance (Stamatakis

et al. 2012).
The VTA receives inhibitory inputs from Locus Coerulus (LC) and Dorsal
Raphé (DR) in the form of noradrenergic and serotonergic projections respectively.
Increased LC release of norepinephrine (NE) onto VTA via chronic optogenetic
activation of LC projections of VTA leads to decreased VTA DA activity and
makes susceptible mice resilient to CSD (Isingrini et al. 2016). The mechanism of
action of NE released from LC is via activation of a1 and b3 noradrenergic
receptors on DA cells projecting to NAc (Hongxin Zhang-unpublished
observations).
The Lateral hypothalamus sends glutamatergic, GABAergic and/or peptidergic
(Orexin/Hypocretin and Neurotensin) inputs to VTA. Previous studies showed that
LH GABAergic projection to VTA increases feeding behaviour, while activation of
LH glutamatergic projection to VTA regulates inputs to VTA (Nieh et al. 2016).
Glutamatergic input from LH to VTA was shown to induce conditioned place
avoidance, attenuate social interaction and decrease DA release in NAc as it targets
the interneurons in the VTA. Conversely, GABAergic input from LH to VTA was
shown to induce conditioned place preference, social interaction and increase DA
release in NAc as it leads to the disinhibition of VTA interneurons to encode
rewarding behaviour. Therefore, evidence suggests that the net effect of the LH
inputs on VTA encodes rewarding behaviour (Nieh et al. 2016).
Moreover, VTA DA neurons receive potent inhibitory inputs from the Ventral
Pallidum (VP) and the basolateral amygdala (BLA), a region associated with stress
and fear learning, sends excitatory glutamatergic inputs to the VP (Napier et al.
1994; Sesack et al. 2010). As previously described in relation to stress, DA and
depression, acute stressors initially activate the DA system, followed 24 h later by
potent attenuation of DA activity. Complex afferent polysynaptic inputs involving
the BLA-VP circuit may in part be responsible for decreased VTA DA activity
during encoding for the different temporal aspects of depression in stress suscep-
tible mice following (CMS) exposure (Goldwater et al. 2009). Evidence of the
BLA-VP-VTA circuit in modulating depression-related behaviours comes from
findings showing (a) reversal of decreased VTA DA activity in CMS susceptible
rats following blockade of excitatory glutamatergic inputs to the VP (thus removing
feed forward inhibitory input from the VP to the VTA), and (b) pharmacological
activation of BLA decreases VTA DA activity (Chang and Grace 2014).
A thorough understanding of the dopamine pathways in the brain is therefore
crucial for designing selective pharmacological modulation of dopamine release in
various diseases such as schizophrenia and mood disorders and to reduce the
prevalence of side effects of current treatments.
Increasing evidence shows that the NAc, a region typically associated with
reward-related behaviours, has a critical role in depression symptomology including
reduced motivation and anhedonia (Krishnan et al. 2007; Nicola 2007; Lobo and
Nestler 2011; Berton et al. 2006; Russo and Nestler 2013). Medium spiny neurons
(MSNs) of the NAc and dorsal striatum are enriched in D1 or D2 receptors and they
send distinct projections to basal ganglia and reward structures. NAc D1-MSNs
send projections to ventral pallidum, globus pallidum, VTA and substrantia nigra
(SN), while NAc D2-MSNs send projections to ventral pallidum (Lobo and Nestler
2011; Smith et al. 2013). These two neural populations work in concert to promote
normal behaviour while imbalance in one sub-type can promote dysfunctional
motivational states (Lobo and Nestler 2011; Francis et al. 2015; McDevitt et al.
2014; Shen et al. 2008). The network balance model demonstrates that activation of
D1-MSNs leads to positive reward behaviour while activation of D2-MSNs leads to
aversive behaviours (Lobo and Nestler 2011; Smith et al. 2013; Shen et al. 2008;
Hikida et al. 2010). Exposure to chronic social defeat was shown to differentially
induce expression of the transcription factor delta FosB in the NAc MSNs. Mice
susceptible to CSD stress expressed elevation of delta FosB in D2-MSNs while
those resilient to CSD stress expressed elevation of delta FosB in D1-MSNs (Vialou
et al. 2010). Furthermore, anhedonia following restrained stress is mediated by
decreased excitatory synaptic strength of NAc D1-, but not D2-MSNs (Lim et al.
2012). These findings were further extended in a recent study where mice sus-
ceptible to CSD exhibited decreased excitatory synaptic inputs into D1, but not
D2-MSNs and that chronic chemogenetic attenuation of D1-MSNs, but not
D2-MSNs, activity induced depressive-like behaviours in mice previously resilient
to CSD stress (Francis et al. 2015). Furthermore repeated optogenetic activation of
D2-MSNs induced depressive-like behaviour in mice exposed to a subthreshold
social defeat paradigm (Francis et al. 2015). These findings are exciting as it
demonstrates: (a) two distinct circuit mechanisms within the NAc encode for
depressive-like behaviours; and (b) changes in synaptic signaling in NAC MSNs
circuit most likely require long-term molecular changes in order for the expression
of depression-like behaviours since chronic, but not acute, optogenetic and
chemogenetic manipulations were required to induce susceptibility to stress. The
transcription factor delta FosB regulates transcription of numerous genes in the
NAc (Kelz et al. 1999; Vialou et al. 2010). Two target genes of delta FosB, AMPA
glutamate receptor subunit GluR2 and Sparc-like 1 (SC1) are upregulated in the
NAc of mice resilient to CSD stress (Vialou et al. 2010). Furthermore, CHIPsec
analysis showed significant binding of delta FosB on the GluR2 promoter and
qPCR analysis revealed sustained GluR2 mRNA in NAc of resilient mice (Vialou
et al. 2010). GluR2 subunit has profound effects on AMPA receptor function, where
GluR2-lacking AMPA receptors are Ca2+-permeable and show greater receptor
conductance and strong inward rectification, as compared to GluR2-containing
AMPA receptors (Liu et al. 2000; Bredt and Nicoll 2003). This switch to
GluR2-lacking AMPA receptors increases neuronal excitability (Isaac et al. 2007).
Electrophysiological measure showed decrease in both GluR2-mediated currents
and increased inward rectification in stress susceptible, but not stress resilient mice,
further implicating increased excitability, in a subset of NAc neurons, encodes for
depressive-like behaviour (Vialou et al. 2010). Several brain regions that mediate
aspects of motivated, goal-directed, behaviours such as the ventral subiculum of the
hippocampus, amygdala and prefrontal cortex send overlapping projections to the
NAc where these inputs are integrated under dopaminergic modulatory control
(Grace et al. 2007). These differential inputs onto MSNs together in addition to the
differential modulatory role of DA on D1 and D2 direct and indirect pathway

highlight the complex interplay of DA with other neurotransmitters in regulating
behavioural processes. Furthermore, changes in the balance of DA inputs onto NAc
can lead to drastic changes in cognition and emotional state.
Furthermore, systems level analysis has shown that DA receptor subtypes dif-
ferentially regulate inputs to the NAc from the limbic system and PFC, where for
example, tonic D2 receptor activation selectively attenuated inputs from the mPFC
while phasic DA activity increases NAc neurons responsiveness to limbic inputs via
activation of D1 receptors (Goto and Grace 2005a, b; O’Donnell and Grace 1994;
West and Grace 2002). Aberration in the balance between these various inputs to
the NAc are believed to lead to the pathophysiology of motivated behaviours such
as addiction and depression. A recent study using a combination of in vivo elec-
trophysiology recordings in rats that had previously undergone a learned help-
lessness depression paradigm showed decreased synaptic input from the vSub into
the NAc of rats susceptible to the depressive phenotype, and not to the resilient ones
(Belujon and Grace 2014). Furthermore, administration of the novel antidepressant
ketamine both rescued the depressed phenotype in rats previously susceptible to the
learned helplessness paradigm and also increased the vSub synaptic input to the
NAc in these rats (Belujon and Grace 2014). At the microcircuit level decreased
synaptic activity from vSub projections to the NAc shell but not NAc core
specifically induced the depressed phenotype (Bredt and Nicoll 2003). The
observations that VTA DA neurons projecting to NAc exhibit increased phasic
firing in stress susceptible mice (Chaudhury et al. 2013) and that, the corti-
cortrophin releasing factor (CRF) gates brain derived neurotrophic factors (BDNF)
signaling in NAc MSNs (Walsh et al. 2014a) shed light on a potential mechanism
by which increased BDNF induces changes in inhibitor of kappa kinase
(IKK) enzyme activity leading to associated changes in dendritic spine morphology
in the NAc of stress susceptible mice (Russo et al. 2010; Russo and Nestler 2013).
The lateral habenula (LHb) is a complex structure that plays a role in beha-
viourally complex functions such as sleep, pain, stress and reward. Even though the
projections from LHb to VTA and DRN are excitatory, its stimulation leads to
inhibition of serotonergic and dopaminergic neurons (Christoph et al. 1986; Wang
and Aghajanian 1977; Matsumoto and Hikosaka 2007). The LHb also receives
serotonergic and dopaminergic input since they express both D2 receptors and
5-hydroxytryptophan 2c (5-HT2c) receptors (Mengod et al. 1990; Aizawa et al.
2012). Presumably, chronic activation of DA inputs to LHb following stress
exposure could hyperpolarize LHb neurons then lead to direct attenuation of
VTA DA cells projecting to mPFC but not NAc. Furthermore, the plasticity in the
projection of VTA DA neurons to the dentate gyrus (DG) in the hippocampus might
be involved in addiction since behavioural analysis showed that morphine-induced
conditioned place preference (CPP) requires NMDAR activation in VTA and
VTA-Hippocampus DG activity (Hu et al. 2014). Since both addiction and
depression are comorbid, it would be interesting to further investigate this pathway
in the context of depression.
The plasticity related changes have been observed in the form of homeostatic
changes within neural circuits related to depression. Recent advances have high-
lighted possible mechanisms that determine the brain’s ability to cope with stress.
As described previously, multiple lines of evidence implicate dysregulation in the
brain’s reward circuit in depression (Blaze and Roth 2013; Valenti et al. 2012; Han
and Friedman 2012; Lobo and Nestler 2011; Maia and Frank 2011). Increased
activity of VTA DA neurons has been causally linked to depression-related beha-
viours (Chaudhury et al. 2013; Valenti et al. 2012; Han and Friedman 2012), where
for example increased activity of VTA DA neurons, in stress susceptible mice, is
intrinsically induced by up-regulation of Ih, an excitatory driving force of VTA DA
neurons (Chaudhury et al. 2013; Levine et al. 2012; Xie et al. 2013), while phar-
macological reduction of increased Ih in susceptible mice reverses depression
(Chaudhury et al. 2013). Furthermore, chronic antidepressant treatment with
fluoxetine normalizes this hyperexcitability and decreases Ih in these neurons
(Chaudhury et al. 2013). Together, these observations suggest that VTA DA neuron
hyperactivity and increased excitatory Ih are both pathophysiological changes in
mice susceptible to stress. A recent study confirmed that upregulation of Ih current
in VTA DA neurons induced increased activity in these neurons in stress suscep-
tible mice (Friedman et al. 2014). Surprisingly, while in resilient mice activity of
these neurons was found to be normal, Ih current was even higher, which was
observed in parallel with increased potassium (K+) current (Friedman et al. 2014).
The role of Ih current on mediating the resilient phenotype was determined by
overexpression of the hyperpolarization-activated and cyclic nucleotide-gated
channel 2 (HCN2), which mediates Ih current, in VTA DA neurons in susceptible
mice. The enhancement of Ih current in previously susceptible mice due to over-
expression of HCN2 channel is accompanied by compensatory upregulation of
inhibitory K+ currents, leading to normalization of the firing rate of the hyperactive
neurons in susceptible mice and inducing the resilient phenotype. Moreover,
repeated optogenetic activation of VTA DA neurons in susceptible mice, that
presumably exhibit hyperactivity, was shown to induce the resilient phenotype
together with associated decreased spontaneous activity and increased K+-currents
in these cells (Friedman et al. 2014). Furthermore, this was observed specifically in
VTA DA neurons projecting to NAc but not mPFC, which correlates with previous
projection-specific role in encoding for depression (Chaudhury et al. 2013).
Previous molecular analysis had shown that mice resilient to CSD stress exhibited
normalized firing activity in VTA DA neurons associated with a corresponding
increase in genes coding for subtype of K+ channels (Han and Friedman 2012). In
primary neuronal cultures, excessive hyperactivity has been shown to induce
homeostatic upregulation of inhibitory driving force K+-mediated currents (Zhang
and Shapiro 2012). Therefore, K+ channels have been considered as new thera-
peutic targets to naturally mediate active stress-coping or resilience. Overexpression
of KCNQ-type K+ channel opener or intra-VTA infusion of KCNQ openers lead to
normalization of the depressive-like behaviours an neuronal hyperexcitability
(Friedman et al. 2016). In line with these homeostatic plasticity changes related to
mood regulation, the previously discussed findings that chronic activation of
LC-VTA projection induces the resilient phenotype was shown to be caused by the
following homeostatic plasticity related to enhancing the excitatory current Ih and
the inhibitory K+-currents in VTA DA cells.
In conclusion, homeostatic plasticity plays a fundamental role in stabilizing
neuronal activity in response to excessive perturbations under both physiological
(Non et al. 2014; Meaney 2001) and disease conditions (Francis et al. 1999).
Observations that VTA DA neurons of resilient mice exhibit upregulation of the
excitatory driving force Ih and inhibitory driving force K+-current suggests
homeostatic plasticity plays a fundamental role in normalizing the neuronal
hyperactivity in promoting natural resilience to stress. Further investigations into
homeostatic adaptive mechanisms in DA pathway leading to natural resilience have
potential implication in the development of more naturalistic treatment strategies for
mental disorders such as depression.
3 Circadian and Sleep Rhythms, Depression

and Dopamine
Growing evidence implicates that mood disorders are closely linked to biological
rhythms that govern physiological and molecular processes at the cellular and
neural circuit level. A variety of neurotransmitters are implicated in mood disorders
including, but not just limited to 5-HT, orexin, noradrenaline, GABA, glutamate
and dopamine have been shown to undergo circadian oscillations and also play a
role in sleep-wake processes. We will first describe processes involved in circadian
rhythms and sleep, then integrate this into rhythmic regulation of Dopamine and
how it relates to mood disorders such as depression.
4 Circadian Clock
Mammalian physiology and behaviour are coordinated by an intrinsic clock into

rhythms that are synchronized with a 24-h solar day. Circadian synchronization
allows anticipation of regular environmental changes to influence a wide variety of
molecular processes and behavioural decisions that impact fitness and survival such
as evasion of DNA damage from environmental insult, food intake, metabolism and
predator/prey interaction (Lowrey and Takahashi 2004; Partch et al. 2014). In short,
circadian rhythms allow an animal to achieve temporal homeostasis with its envi-
ronment at the molecular level by regulating gene expression such that rhythmicity
in the expression of various genes leads to subsequent oscillations in the down-
stream molecular pathways around a 24-h cycle. Those rhythmic physiological
processes include the cardiovascular activity, sleep/wake cycle and neural
activity-brain function that eventually leads to the regulation of behaviour and
metabolism. Nearly every cell in the body genetically encodes a molecular clock
that generates an approximately 24-h internal timing in the absence of external cues
(Yamazaki et al. 2000). Furthermore, these molecular oscillatory clocks located
throughout the body are organized into a coherent, hierarchical system by a ‘master
clock’ located in the suprachiasmatic nucleus (SCN) of the hypothalamus (Partch
et al. 2014; Ko et al. 2006). The SCN, a highly unified circadian network composed
of approximately 20,000 neurons (Partch et al. 2014; Mohawk and Takahashi
2011), is the only molecular clock to receive light input from the retina that syn-
chronizes internal clock timing to the external solar day which is then transmitted to
the secondary peripheral clocks via endocrine and systemic cues (Partch et al. 2014;
Buhr and Takahashi 2013; Dibner et al. 2010). The central circadian oscillations of
clock genes and their products within the suprachiasmatic nucleus generate daily
rhythms in behaviour and physiology (Weil and Nelson 2014). Studies in droso-
phila clock cells showed that circadian regulation of clock cell activity is via
increasing expression of voltage-independent sodium channels leading to increased
Na+ conductance and depolarization during the day and consequent increased
activity in clock neurons while at night, basal K+ current increases leading to
attenuation of clock neuron activity. Furthermore, CLOCK protein rhythmically
binds to and activates transcription of genes important for proper axonal localiza-
tion of Na+ channels (Flourakis et al. 2015). Though the molecular clock in the
SCN and secondary peripheral cells express similar molecular architecture and
ability to generate rhythms, a key difference between the SCN master clock and
peripheral oscillators in the rest of the brain and body is the high degree of inter-
cellular coupling between neurons of the SCN that is resistant to perturbations from
internal cues (Partch et al. 2014; Buhr and Takahashi 2013; Liu et al. 2007). In
contrast, rhythms in secondary oscillators are sensitive to signaling from the SCN
via circulating hormones, metabolic cues and systemic changes such as body
temperature (Ralph and Block 1990; Yang et al. 2007; Brown et al. 2002; Saini
et al. 2012). The circadian clock network ensures that the SCN robustly maintains
approximately 24-h timing to maintain temporal coordination with the external
solar cycle while secondary oscillators adept to reflect local metabolic status of the
tissue (Partch et al. 2014; Stratmann and Schibler 2006). Thus, input signals from
light to the clock leads to a synchrony between the physiology and the surrounding
natural events thus allowing an organism to optimally interact and be in phase with
its environment (Ralph and Block 1990). Once the circadian clock and the external
environment are out of phase, desynchronization of the different physiological
processes in the body occurs leading to disorders as depression and obesity (Hampp
et al. 2008).
Light activation of photoreceptors (rods and cones) on the retina enables us to
generate images of our world. There are also an additional subset of photoreceptors
in the retina that can influence behaviours and mood. Light modulation of mood
occurs through activation of a subset of non-imaging photoreceptors in the retina
called intrinsically photosensitive retinal ganglion cells (ipRGC). Retinal ganglion
cells are part of the retinal circuitry, the majority of which receive visual infor-
mation from photoreceptors via two intermediary neurons, the bipolar and amacrine
cells. A small minority of retinal ganglionic cells express the photopigment mel-
anopsin that have been shown to respond intrinsically to light in the absence of rods
and cones and are termed ipRGC. Evidence for the existence of these non-imaging
forming photoreceptors comes from observations such as (a) light exposure to blind
humans, who were unable to form images, could still inhibit melatonin secretion
(Czeisler and Dijk 1995; LeGates et al. 2014) (b) genetically modified mice lacking
image forming rods and cones were still able to photo-entrain to light (LeGates
et al. 2012, 2014; Freedman et al. 1999). The image forming retinal ganglionic cells
project to the visual cortex and associated image forming regions of the brain while
ipRGC project to the (a) the central circadian pacemaker the SCN, (b) ventrolateral
preoptic nucleus (vLPO) and lateral hypothalamus which are important in
sleep-wake regulation and (c) brain regions implicated in mood regulation (LeGates
et al. 2014; Schmidt et al. 2011). These diverse projections of the ipRGC highlight
a potential circuit, and thus cellular mechanism, by which light mediates effects on
several behaviours such as circadian rhythms, sleep, alertness and mood (LeGates
et al. 2014). The VTA, is part of the reward system (Ulery et al. 2006) and receives
indirect inputs from the SCN via a variety of pathways. For example circuit-tracing
studies found that (a) SCN indirectly projects to VTA via the medial preoptic
nucleus (MPON) (Gervasoni et al. 2000) and (b) the VTA neurons exhibited cir-
cadian rhythmicity in their activity such that VTA cells were selectively active
during the active circadian phase (Luo and Aston-Jones 2009). The MPON nuclei
are sleep active and given that majority of its projections are inhibitory, activation
of MPON during sleep leads to inhibition of VTA neurons. Conversely, during the
active phase (nocturnal for rodents) the decreased activity of MPON nuclei leads to
disinhibition of VTA cells leading to increased activity during awake state.
The VTA has been implicated in sleep-wake regulation where for example an early
study found that lesioning of VTA decreased arousal (Jones and Gubbins 1973),
while later studies showed that VTA neurons exhibited diurnal variability in
activity (Luo and Aston-Jones 2009) and also variability in activity in relation to
arousal states. A recent study showed in fact that VTA DA neurons exhibit
intra-diurnal rhythmic activity in anesthetized rats where basal activity was highest
at two time points between 07:00–11:00 h and 19:00–23:00 h while lowest activity
was measured between 11:00–15:00 h and 23:00–03:00 h (Dominguez et al. 2014).
The highest number of spontaneously active VTA DA neurons were measured
between 03:00–06:00 h, which is not too surprising as rodents are nocturnal and
they are most likely active at these time points.
The transcription of monoamine oxidase (MAOA), which catalyzes the oxida-
tion of monoamines such as dopamine, is regulated by circadian clock genes.
Specifically, circadian clock transcription factor proteins BMAL and NPAS2 reg-
ulated monoamine oxidase promoter. Per2 mutant mice exhibited decreased
expression of MAOA in mesolimbic DA neurons of the VTA. Per2 mutant mice
also exhibit increased DA levels in the NAc, most likely due to the attenuated
breakdown of DA because of decreased activity of MAOA (Hampp et al. 2008).
Earlier studies had shown that (glycogen synthase-3) GSK3 directly phosphorylates
5 core clock proteins (McClung 2007)—PER2, CRY2, CLOCK, BMAL1 and
VTA neuron NAc neuron
Glu
Ca2+
Ca2+ Calmodulin SubstrateP
CRF
Degradation Nucleus
P ROR DA
Bmal1 Transcriptional
Rev-Erb BMAL Repression
P BDNF
Bmal1 TH Block Transcrption of TH
CLOCK
CRE Transcript Circadian
GSK-3β
MAOA [Ca2+]i CAM CAM CREB P Clock Gene
E-box MAOA Cck CamkIV
P
Per2 Per2 Bmal1 NPA2 DA DA GSK-3β GSK Target
GSK-3α
E-box K+ Channel
AKT
Bmal1 CLOCK
Cck
DA PP2A
CcK Cck
CLOCK Nucleus
Cytoplasm Cytoplasm
K+ Channel AMPA receptor
CcK receptor NMDA receptor
P1 receptor D2 receptor
ATP ADP AMP Adenosine TrKB receptor Ih channel
Fig. 1 Graphical representation of some of the molecular pathways linking circadian and sleep-wake
signaling with the molecular pathways related to neural activity/plasticity that may result in regulation
of mood. Cck = Cholecystokinin, REV-ERBa = Circadian Clock Protein, BMAL1 = Circadian Clock
Protein, CLOCK = Circadian Locomotor Output Cycles Kaput Protein, CRY = Cryptochrome, PER =
Period, NPAS2 = Neural Pas Domain Protein, TH = Tyrosine Hydroxylase, K+ = Potassium Channel,
Ih = hyperpolarization-activated non-selective cation channel, NMDA = N-methyl-D-aspartate
receptor, AMPA = a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, MAOA = Monoamine
Oxidase A, DA = Dopamine, BDNF = Brain-derived Neurotrophic Factor, GSK-3 = Glycogen
Synthase 3, D1 = Dopamine-1 Receptor, D2 = Dopamine-2 Receptor, CRF = Corticotropin-Releasing
Factor, CAM = Calmodulin, CamKIV = Ca2+/Calmodulin-Dependent Protein Kinase IV, CREB =
cAMP Response Element Binding Protein, CRE = cAMP Response Elements, PP2A = Protein
Phosphatase 2A, AKT = Protein Kinase B, bArr2 = b-Arrestin
REVERBa. Furthermore, enhanced expression of the active form of GSK3b

induces the susceptible phenotype following CSD stress (Wilkinson et al. 2011).
Figure 1 illustrates the regulation of transcription and translation of the various
CLOCK proteins and how aberration in the expression might induce the susceptible
phenotype by affecting the DA transmission. D2 receptor activation on MSN NAc
neurons inhibits Akt activity, which has an inhibitory effect on GSK3b activity. In
other words, D2 activation leads to disinhibition of GSK3b and induction of the
susceptible phenotype following CSD (Beaulieu 2012). It has been hypothesized
that an imbalance between D1 and D2 activity may lead to schizophrenia and other
mental disorders based on previous evidence that D1 hypoactivity in the mPFC is
associated with D2 hyperactivity in the striatum in schizophrenic patients (Francis
et al. 2015). Furthermore, based on previous findings that the imbalance between
D1 and D2 inputs leads to the depressive phenotype, it would be interesting to
explore the imbalance in GSK3b phosphorylation in D1 and D2 pathways in NAc
in the depressive phenotype (Jope and Roh 2006). Moreover, Clock-knockout mice
exhibited increased Tyrosine hydroxylase (TH) level, which potentially suggests

that VTA CLOCK proteins inhibit DA synthesis (McClung et al. 2005). TH is the
enzyme responsible for L-DOPA synthesis, which the precursor of DA. Diurnal
expression of TH expression and hence the availability of DA in VTA and NAc was
demonstrated by measuring reward-associated change in TH level throughout the
day (Webb et al. 2009). Peak drug reward coincided with peak TH levels, which in
light of the known comorbidity of addiction and depression, points to additional
mechanism by which the circadian system my modulate mood. These findings
constitute the foundation for chronotherapeutics, a strategy of administering treat-
ment at times that correspond to a person’s circadian cycle to maximize effec-
tiveness and minimize side effects. Per1, clock gene, expression is region specific,
which suggests that the different behaviours regulated by different brain regions will
exhibit different rhythms and the effectiveness of manipulating such behaviours will
depend on the time of the day (Cardasis et al. 2007). In a Zebra fish model of
ADHD with a mutation Per1b (ortholog of human Per1 gene), there is a decrease of
DA neuron number along with sparse and irregular distribution of DA neurons
(Huang et al. 2015; Ablikim et al. 2015), which further supports the notion of
linking CLOCK protein and DA in relation to psychiatric disorders.
Transcription factor nuclear factor kappa B (NfkB) is upregulated in the striatum
following repeated cocaine administration (Russo et al. 2009; Ang et al. 2001).
Additionally, the circadian nuclear factor receptor, REV-ERBa, which represses
transcription of BMAL1, has a key role in regulating TH expression and consequently
has been shown to regulate both DA levels and mood behaviour (Chung et al. 2014;
Arey et al. 2014). Circadian disruption in VTA DA cells of Clock mutant mice shows
that CLOCK protein regulates TH transcription and Cholecystokinin (Cck), a peptide
negatively associated with DA activity in vivo, which has been implicated in anxiety
and drug response (Arey et al. 2014; Sidor et al. 2015). CLOCK protein is a tran-
scription factor for the Cck gene leading to increased expression of Cck. Clock KO
mice have decreased Cck in VTA DA cells. In the VTA and SN, Cck is highly
co-localized with DA, Additionally, Cck is co-released with DA from VTA DA cells
projecting to NAc, especially during phasic firing as it is a negative modulator of DA
transmission (Broms et al. 2011; Ren et al. 2009). Moreover, in wild type mice,
CLOCK protein is a negative regulator of TH activation, thus Clock mutant mice
express high levels of DA in NAc and are more resilient to CSD stress but also exhibit
mania like behaviours (Ozburn et al. 2012, 2013; Roybal et al. 2007).
5 Sleep
Sleep is defined as a readily reversible state of reduced responsiveness to, and inter-
action with, the environment. Though clearly important, as evidenced by the fact that
all animals require sleep to some degree, the functional role of sleep is still not well
understood. Current evidence so far implicates a role for sleep in numerous processes
such as attention and problem solving, learning and long term memory formation, and
development and proper functioning of the immune system (Pellaprat et al. 2014).
Sleep is regulated by a combination of homeostatic and circadian processes (Borbely
1982; Daan et al. 1984). The oscillating output of the circadian system gives time
context to various physiological processes and behaviours including sleep, and ensures
proper entrainment of internal rhythms to the daily light-dark cycle such that the
distribution of sleep over the 24-h cycle is strongly determined by the circadian
system. In contrast to the internally generated and self-sustained oscillations of the
circadian clock, the homeostatic process of sleep regulation tracks sleep need such that
sleep need and the propensity to sleep increase during wakefulness and decrease
during sleep (Franken and Dijk 2009). The daily circadian-influenced rhythms in the
sleep-wake cycle would appear to make the homeostatic processes driving sleep-wake
as a 24-h rhythm though an important distinction is that the 24-h homeostatic influence
on sleep-wake cycle is driven by the distribution of sleep-wake states such that the
oscillation can be considered as an ‘hour-glass’ oscillator while the circadian rhythms
on sleep is a self sustained oscillation (Franken and Dijk 2009). Homeostatic sleep and
SCN
SPZ LHb Circadian

Sleep
Regulation Regulation
DMH RMTg
vLPO PPTg LDT
VTA DR
LC
Unknown
5-HT neuron
Mood GABA neuron
Dopamine neuron
Regulation
Glutamate neuron
Vasopressin neuron
Acetylcholine neuron
Norepinephrine neuron
Fig. 2 Graphical representation of the neural circuit linking the circadian and major sleep-wake
centers to regions of the brain associated with mood regulation. SCN = Suprachiasmatic nucleus, SPZ
= Subparaventricular Zone, DMH = Dorsal Medial Nucleus of the Hypothalamus, vLPO =
Ventrolateral Preoptic Nucleus, VTA = Ventral Tegmental Area, LC = Locus Coeruleus, DR = Dorsal
Raphe, PPTg/LDTg = Pedunculopontine Tegmentum/Laterodorsal Tegmentum, RMTg =
Rostromedial Tegmental Nucleus, LHb = Lateral Habenula
circadian sleep are generated independently but interact closely (Dijk and von Schantz
2005). The first conformation for this two-process model came from studies where
sleep-wake cycles of human subjects were forced to desynchronize from endogenous
circadian rhythms (Dijk and Czeisler 1994, 1995). Findings from these studies suggest
that the circadian system generates rhythms in sleep-wake propensity that is timed to
oppose the homeostatic changes in sleep drive such that we are able to stay awake and
alert throughout the day despite the accumulation of sleep need while conversely stay
asleep during the night despite the decrease of sleep need (Dijk and von Schantz
2005). Though sleep homeostasis and circadian systems are closely linked as
described in the two process model, experimental evidence suggests that they are also
functionally and anatomically autonomous processes. For example, lesion of the SCN
rendered animals arrhythmic but did not affect the sleep deprivation induced increase
in delta slow wave sleep (Franken and Dijk 2009; Larkin et al. 2004; Easton et al.
2004; Trachsel et al. 1992). Though there is evidence for separation of some aspects of
sleep and circadian rhythm, accumulating data suggest significant cross-talk between
the homeostatic and circadian processes. Figure 2 illustrates the overlap between both
circadian and sleep/wake centers in their projections to the brain areas of mood
regulation and their input. For instance, Hamsters exposed to sleep deprivation
(SD) during the dark, active phase show phase shifts in their circadian clock activity
(Antle and Mistlberger 2000). Furthermore, SCN neural activity is decreased during
NREM slow wave sleep (SWS) and is negatively correlated with EEG delta activity
(Deboer et al. 2007; Deboer et al. 2003). Furthermore, significant evidence of the close
association between sleep/wake cycle and circadian rhythms comes from numerous
findings that mutations in circadian clock genes affect aspects of sleep such as
(SWS) EEG activity patterns, sleep time and sleep pressure (Franken and Dijk 2009).
6 Linking Circadian and Sleep: Circuits and Molecular

Mechanisms
The sleep and circadian system are two independent yet closely linked systems
(Mistlberger 2005; Schwartz and Roth 2008; Fuller et al. 2006; Borbely et al.
2016a). Ultradian sleep-wake regulation controlled by basal forebrain/preoptic
(BF/POA) nuclei of hypothalamus while circadian oscillation is controlled by SCN.
The mechanism by which circadian oscillation is integrated with the ultradian
system is unclear. In vivo, neural activity exhibited diurnal rhythmicity and/or
sleep-wake dependence, while acute serotonin (5-HT) depletion in the dorsal raphé
nucleus (DRN) resulted in the decrease in diurnal rhythmicity in neural activity in
the BF/POA but not in SCN. Furthermore, local blockade of (5-HT) transmission in
BF/POA was sufficient to disrupt the diurnal sleep-wake rhythms of mice. This
evidence suggests that the 5-HT system enables the BF/POA to couple to the SCN.
In mammals, the sleep and wake states occur in a precise 24-h cycle that has
evolved as an adaptation to the solar cycle of light and dark (Moore 2007). The
circadian clock drives many physiological and behavioural processes and partitions
behaviours such as sleep to occur at a particular time of the day-night cycle. In
addition to circadian control of sleep, homeostatic mechanisms track sleep need.
Thus, the combination of circadian mechanisms and homeostatic drive determines
the length of sleep (LeGates et al. 2014). This 2-process model of sleep regulation
describes a system where the homeostatic process (Process S), which depending on
sleep and wake duration, interacts with the process controlled by the circadian
pacemaker (Process C), which determines the salient aspects of sleep (Borbely et al.
2016a). Process S, representing sleep debt, increases during wakefulness and
declines during sleep. Though the exact nature of homeostatic sleep debt and its
interaction with the circadian process is still unknown, a simplified model suggests
that during the awake periods accumulation of sleep-promoting substances leads to
an increase in the sleep-drive together with a subsequent decrease in circadian
arousal over the course of the day leading to the initiation of sleep (Borbely et al.
2016a; Moore 2007). The principal marker of Process S during sleep is non-rapid
eye movement (NREM) slow wave sleep activity (SWA) while theta brain activity
represents the decreasing sleep debt. The markers for Process C are rhythms in
physiological function such as core body temperature and melatonin secretion.
The CLOCK protein is a transcription factor that plays a pivotal role in the
molecular pathways that leads to the generation of circadian rhythmicity in the
master clock (the SCN) and other secondary oscillatory cells (Borbely et al. 2016b).
Clock-mutant mice have pronounced change in overall circadian rhythms.
Experiments were performed to determine whether genetic knockdown of CLOCK
affected sleep homeostasis. Findings showed that Clock-mutant mice did not entrain
to 12:12 Light/Dark (LD) cycle and had abnormal free running rhythms in
Dark/Dark (DD) (Naylor et al. 2000). Measurements of sleep homeostasis found
that heterozygote and homozygote Clock-mutants slept one and two hours less in
LD condition and had 25 and 51 % smaller increase, respectively, in REM sleep
during 24-h period sleep recovery following sleep deprivation. Previous data had
shown that clock genes contribute to homeostatic control of sleep regulation, thus
showing that circadian and sleep have reciprocal effects on each other. For example,
mutation in clock genes lead to changes in markers of sleep homeostasis while other
evidence has shown that increasing homeostatic sleep drive changes clock gene
expression (Mongrain et al. 2011). Furthermore, the effect of SD on clock gene
expression had shown that SD affects binding of Clock proteins to core-clock
transcription factors, which in turn can have a feedback effect on sleep and systems
related to learning and memory and mood disorders (Mongrain et al. 2011). Though
the sleep and circadian system are closely linked, evidence that SCN ablation
renders animals arrhythmic but does not disrupt sleep homeostasis (Borbely et al.
2016a) suggests that Process S and C are regulated by distinct mechanisms.
Investigations into the effect of SD induced reversal of depression on these 2
pathways may lead to understanding the mechanisms involved in the expression of

differing symptoms observed in patients.
7 Depression, Circadian Clock and the Sleep-Wake Cycle
One cause for the increase in global depression may be the modern life-style with
increased exposure to artificial light, shift work and travel across time zones, all of
which can disrupt circadian rhythms and the sleep/wake cycle (McClung 2013).
Although it has been known since the 1950s that daily rhythms are disrupted in
patients suffering from depression (McClung 2013; Wirz-Justice and Van den
Hoofdakker 1999), the cellular and molecular mechanisms linking aberration in
circadian/sleep rhythms and mood disorders are still not understood. Patients with
psychiatric illness such as bipolar depression, characterized by extreme changes in
mood, exhibit irregularities in daily rhythms such as activity and numerous phys-
iological parameters (McClung 2007; Mukherjee et al. 2010; Goetze and Tolle
1987; Deshauer et al. 1999; Souetre et al. 1988; Bunney and Potkin 2008).
Maintaining patients on a regular sleep and social schedule has shown to be an
effective treatment strategy for bipolar disorders indicating that aberrations in cir-
cadian or sleep-wake cycle may contribute to mood disorders. Though it has been
known since the 1950s that daily rhythms are disrupted in patients suffering from
major depressive disorder (MDD) (McClung 2007; Wirz-Justice 2006), the
molecular mechanisms linking aberration in circadian/sleep rhythms and mood
disorders is still not well understood. In healthy humans, mood and reward are
modulated by circadian phase (Boivin et al. 1997; Birchler-Pedross et al. 2009).
Mood disorders involve deficits in reward processing and motivation where per-
ception in reward is blunted with a corresponding reduction in motivation to pursue
hedonic goals. Circadian oscillation of gene expression, neural firing, neurotrans-
mitter levels and receptor expression have been discovered in various brain regions
implicated in mood-regulation and reward of both rodents and humans (Sidor and
McClung 2014). The Social Zeitgeber theory of mood disorders proposes that
stressful life events change sleep/wake schedule that alters molecular and cellular
rhythms in vulnerable individuals, leading to mood disorders (Ehlers and Kupfer
1987). For example, chronic unpredictable stress (CUS) induced reversible change
in Per2 rhythms in the SCN (Jiang et al. 2011). Specifically CUS induced damp-
ening of Per2 rhythms in the SCN and two weeks after CUS, Per2 rhythms returned
to normal in SCN but mice still exhibited depressive-like behaviours suggesting
that dampening of Per2 rhythms leads to expression of depressive-like behaviours
but did not affect long-term expression of depression. Additionally, it would be
interesting to understand how the imbalance hypothesis between the D1 in mPFC
and D2 activity in striatum is involved in depression (Francis et al. 2015) and
medial lateral
mPFC VTA OFC
Ih-
LH Amyg
Ih+ CeA BLA
Ih-
PPTg VP
Ih+
Ih-
LDT NAc
Lateral Medial Core
Shell Shell
Ih+
BNST Hipp
LC LHb
RMTg
Glutamate neuron Norepinephrine neuron

Dopamine neuron Acetylcholine neuron
GABA neuron hypocretin neuron
Fig. 3 Graphical representation of neural circuits connecting the dopamine reward region, the
VTA (Ventral Tegmental Area), and regions associated with mood regulation. These reciprocal
connections illustrate how these various regions are able to regulate each other, such that
aberrations in signaling may lead to mood disorders such as depression. mPFC = medial Prefrontal
Cortex, LH = Lateral Hypothalamus, DR = Dorsal Raphe, PPTg = Pedunculopontine Tegmentum,
LDTg = Laterodorsal Tegmentum, RMTg = Rostromedial Tegmental Nucleus, LHb = Lateral
Habenula, Hipp = Hippocampus, NAc= Nucleus Accumbens, BNST = Bed Nucleus of the Stria
Terminalis, VP = Ventral Pallidum, LC = Locus Coeruleus, OFC = Orbitofrontal Cortex, Ih =
hyperpolarization-activated non-selective cation current
whether there is an imbalance in the expression of clock genes in D1 and D2

pathways (Jope and Roh 2006). As demonstrated in Fig. 3, there are various inputs
coming onto and various outputs coming out of VTA at any single moment. It has
been hypothesized that mood regulation depends on the balance between the inputs
and the outputs of VTA. In general, circadian differences in MAPKinase and cAMP
activity (Eckel-Mahan et al. 2008) and responsiveness of pyramidal cells to (NOR),
ACh and 5-HT (Brunel and de Montigny 1987) have been detected in the hip-
pocampus. Finally circadian variations in hippocampal excitability and long-term
potentiation (LTP) have also been detected (Chaudhury et al. 2005), and it would be
interesting to explore whether these variations exist in the depressive phenotype.
Anatomical observations that the SCN projects to the hypothalamus (Bao et al.
2008; Buijs et al. 1993), locus coeruleus (Aston-Jones and Bloom 1981;
Aston-Jones et al. 2001), VTA (Luo and Aston-Jones 2009) and other brain regions
related to stress (Sylvester et al. 2002) together with molecular evidence of circa-
dian dysregulation following stress exposure further highlight potential targets for
the development of novel therapeutics.
Patients suffering from depression more commonly suffer from sleep disturbances
as well as shorter onset latency of REM sleep and longer REM sleep duration
(Schumann et al. 2001). Moreover, it was demonstrated that antidepressants reduced
REM sleep further indicating close association between depression and sleep (Vogel
1975; Slater et al. 1978). Several experiments point to a potential role of LHb in sleep
regulation since lesion in the LHb reduces the duration of REM sleep. Furthermore,
LHb projects to DR, which is a wake-promoting brain region and lesion of DRN
attenuated LHB effects on REM sleep (Aizawa et al. 2013). Additionally, the LHb
sends projections to PPTG and LDTG that send projections to VTA regions and are
implicated in REM sleep. It would be interesting to explore the effect of lesioning LHb
inputs to PPTG and LDTG activity and the effects on sleep.
Classical antidepressant therapies have shown to affect circadian clock functions.
For instance, chronic administration of mood stabilizer lithium in clock mutant
mice reverses the mania-like behaviour (Roybal et al. 2007). In light of the close
interaction between the circadian and sleep/wake rhythms it is therefore not sur-
prising that sleep deprivation therapy (SDT) rapidly alleviates depressive symptoms
(Bunney and Bunney 2012). Studies over several decades have confirmed that SDT
rapidly (within 24 h) reduces depressive symptoms in 40–60 % of patients
(Wirz-Justice and Van den Hoofdakker 1999; Wirz-Justice 2006; Benedetti et al.
2003; Wu and Bunney 1990). However, the drawback with SDT is that the majority
of patients report relapses of depressive symptoms after the first bout of sleep
(Bunney and Bunney 2013; Bunney et al. 2015). Though not yet determined, it is
thought that SDT resets the aberrant circadian clock in depressive patients resulting
in alleviation of symptoms (Bunney and Bunney 2013; Bunney et al. 2015). It is
most likely that a variety of neurotransmitters play a role in the SD induced reversal
of depression and in the context of this review it is interesting to note that DA
agonist prevents the antidepressant effects of SD, which highlight a role for DA
neurotransmission in SD induced reversal of depression (Benedetti et al. 1996).
Accumulating clinical evidence highlights potential changes in circadian clock gene
expression in depressed patients. Molecular analysis of clock genes in suicide
versus non-suicide cases in postmortem found significant downregulation of per1 in
suicide victims (Sequeira et al. 2012). Viral knock-down of mper1/2 gene alone
induced anxiety-like behaviour in mice, suggesting a causal link between aberration
of circadian clock gene expression and anxiety/depression. Stress exposed mice
also exhibited flattened diurnal locomotor activity returning to normal rhythms
seven days post-termination of stress (Slattery et al. 2012). Social defeat in the
middle of the light phase increased both NREM sleep intensity, and duration and
decreased REM sleep (Meerlo and Turek 2001). Though limited in numbers, the
few studies of SDon depression/anxiety have been promising. SD has been shown
to reverse CSD stress-induced anxiety (Meerlo et al. 1996) and induce phase shifts
in circadian clock gene expression (Lavebratt et al. 2010; Kavcic et al. 2011).
Molecular analyses of clock gene expression in mice following SD leads to elevated
Per1 and Per2 levels in cortex, basal forebrain and hypothalamus which returned to
normal levels following recovery sleep (Wisor et al. 2002; Wisor et al. 2008).
Furthermore, SD has been shown to alter (A) DNA binding of specific clock
proteins BMAL, CLOCK and NPAS2 (Mongrain et al. 2011), (B) expression of
various proteins known to be associated with depression such as GSK-3b, AMPA,
Glutamate and mTOR (Bunney et al. 2015) and (C) molecular pathways that have
been shown to play a role in VTA DA-dependent mood regulation. Additionally,
the rapidly acting antidepressant ketamine alters circadian gene expression (Bellet
et al. 2011), intracellular signaling molecule and neurotransmitter levels (Bunney
et al. 2015), and decreases aspects of REM sleep (Gottschlich et al. 2011).
8 Depression, Clock, Sleep-Wake Cycle and Dopamine
The VTA has reciprocal connections with a variety of nuclei. The mPFC, sub-
thalamic nuclei and PPTg/LDTg nuclei send robust excitatory projections to the
VTA that modulates VTA DA cells. Activation of layer V pyramidal neurons that
project to the VTA leads to burst of activation of VTA DA cells, and results in
increased DA release in VTA target sites such as NAc and other forebrain areas
such as the thalamus basal forebrain bundle. In the VTA, glutamate binds to
ionotropic and metabotropic receptors in VTA DA cell bodies and dendrites
(Paquet et al. 1997). A variety of regions that undergo circadian and/or sleep/wake
control in neural dynamics such as the Lateral Hypothalamus (orexinergic), Dorsal
Raphe (5-HT), PPTg/LDTg (Glutamate/Ach), Locus Coeruleus (Noradrenergic)
and basal forebrain receive reciprocal connections with the VTA and input from
these regions onto VTA DA cells is able to influence the role of VTA DA cells on
wake states. Various inputs to VTA can differentially modulate VTA DA and
non-DA cells. For example Orexigernic inputs from the hypothalamus excite
VTA DA and non-DA cell (Korotkova et al. 2003), while the alpha-2 (a2) nora-
drenergic receptor activation converts irregular and burst activity of VTA DA
neurons to tonic pacemaker-like activity (Grenhoff and Svensson 1989). The 5-HT
on the other hand has a dose-dependent effect on VTA DA activity, where low
dosage of 5-HT increases VTA DA firing rate and bursting dynamics while high
doses of 5-HT decrease VTA DA activity (Pessia et al. 1994; Gervais and Rouillard
2000). The orexin neurons of the LH play an integral role in modulating the
sleep-wake cycle, by specifically modulating the monoaminergic pathways (LC,
tuberomammillary nucleus [TMN] and DRN) in the flip-flop model of sleep (Saper
et al. 2005). Typically, orexinergic neurons of the LH are active during wakeful-
ness, particularly during motor activity when animals are exploring their environ-
ment (Estabrooke et al. 2001; Mileykovskiy et al. 2005; Lee et al. 2005). Therefore,
it is intriguing to investigate the disturbance of the GABAergic input from LH onto
VTA and of the orexin input on the flip-flop circuits caused by sleep deprivation
and its effect on depression.
The role of DA in arousal was initially proposed by Jones et al. (Jones et al.
1973; Smith et al. 1998) who found that lesioning of DA cells in VTA and SNc of
cats induced behavioural states characterized by akinesia, hypertonus and decreased
arousal. However, due to the general lack in lesion specificity, it was hard to solely
ascribe a role for DA in these behaviours. More recent genetic targeting of DA
receptors has begun to unravel the specific roles of DA in regulating various aspects
of behaviour, in particular its role in modulating motivation, mood and sleep. For
example, knocking out D1 subtype receptors (D1 KO mice) induced decreased
movement initiation, reaction time to external stimuli and grooming bouts (Smith
et al. 1998; Cromwell et al. 1998). Knocking out D1 receptors decreased sponta-
neous activity and impaired motor coordination (Baik et al. 1995; Kelly et al. 1998;
Vallone et al. 2002). Overall findings from these studies implicate a role for D1 and
D2 receptors in modulating behavioural arousal. The role of DA in regulating sleep
has come from a variety of studies using: (a) transgenic mice lacking DAT trans-
porter thus resulting in increased DA activity in the synapse, (b) Neurotoxin
induced loss of DA cells in VTA and SNc and (c) pharmacological manipulation of
DA receptors. In studies where dopamine transporter (DAT) was knocked out in
mice both homozygous and heterozygous mice exhibited increased awake time and
decreased NREM sleep during the light phase (Wisor et al. 2001). Though sleep
was affected, it was observed that circadian rhythms in these mice could be
entrained to a 12:12 LD cycle, though wheel running was increased during the light
phase (Francis et al. 1999; Wisor et al. 2001). These observations that increasing
DA levels activity, by decreasing reuptake, affect sleep-wake cycle but not circa-
dian entrainment further suggest that the circadian and sleep-wake systems, though
overlapping, are separate systems. Furthermore, it is notable that increasing
synaptic DA levels in DAT KO mice also leads to robust antidepressant effects
when measured on the forced swim test (FST—decreased immobility and increased
climbing and swimming), tail suspension test (decreased immobility) and an
increase in sucrose preference i.e., reduced anhedonia (Perona et al. 2008). Thus,
observations that increasing synaptic DA levels affect sleep by increasing wake
time and reducing NREM sleep during the light phase while also alleviating the
depressive phenotype point to a possible mechanism by which sleep deprivation
leads to rapid alleviation of depressive symptoms. Pharmacological manipulations
have further highlighted the role of DA and the subtypes of receptors in sleep and
wake states. For example in rats, D1 agonist has been shown to desynchronize
EEG, increase wake states and arousal while at the same time decreasing slow wave
sleep and REM sleep (Coffin et al. 1989; Kropf and Kuschinsky 1993). Conversely,
D1 antagonist decreased wake states and increased SWS and REM (Monti et al.
1990). Administration of D1 agonist in human subjects leads to increase in NREM,
delta EEG and mean burst duration of sleep spindles though notably wake and
REM duration were not effected (Eder et al. 2003). D2 receptors can be pre- or
post-synaptic and pharmacological manipulation led to differential responses
depending on the subtype of D2 receptor activated. For example D2 pre-synaptic
autoreceptor activation leads to decreases in locomotor activity and increases in
behavioural sleep and EEG sleeping pattern (Monti et al. 1988). Furthermore, other
studies had shown that low doses of D2 agonist decreased wake states and
increased SWS and REM while high doses of D2 agonist increased wake states and
decreased SWS and REM (Monti et al. 1988, 1989). It is hypothesized that the
biphasic effect of D2 receptor activation is due to differential pre-synaptic autore-
ceptors or post-synaptic activation such that low doses activates D2 autoreceptors
leading to inhibition of further DA release while high doses activate post-synaptic
receptors that also leads to hyperpolarization of cell. Though D2 receptor activation
attenuates cell activity, a proposed mechanism by which D2 activation induces the
wake states involves D2 receptor activation on GABAergic MSN neurons pro-
jecting to the mPFC leading to removal of the inhibitory input to the mPFC and
increased activity in the mPFC (Seamans et al. 2001). Further evidence of the role
of dopamine in wake and arousal states is observed in Parkinson’s patients with
depletion of DA in SNc where these patients suffer from excessive sleepiness
(Pellaprat et al. 2014). Overall the findings that stimulation of PPTg/LDTg, DRN,
LC and LH induces waking in sleeping animals may in part be due to excitatory
modulating effects from these nuclei unto VTA DA cells that induce a change in
bursting activity in VTA DA cells (Monti and Monti 2007). Genetic evidence in
bipolar patients suggests that the central transcriptional activator of molecular
rhythms, CLOCK, may play a pivotal role in the disease (Yeim et al. 2015).
Furthermore, Clock-mutant mice express behavioural profiles similar to mania such
as hyperactivity, decreased sleep, lowered depression-like behaviour, lower anxiety
and increased cocaine and sucrose preference (Roybal et al. 2007). The effects of
social defeat stress on circadian rhythms and sleep have been investigated (Meerlo
and Turek 2001; Meerlo et al. 2002), where they found that 1-h social defeat in the
middle of the light phase (mouse sleeping time) lead to increased NREM sleep
intensity (for about 6 h) and NREM sleep duration (12 h) and suppression of REM
sleep (Meerlo and Turek 2001). One of the components of NREM sleep is SWS
that results in deep sleep. SD leads to rebound of SWS which may in part explain
the return of depressive phenotype reported by patients following rebound sleep
(after SD treatment). At the neural circuit level, during SWS, VTA GABA cells
activity is decreased which may lead to increased VTA DA cell activity (Lee et al.
2001). Thus, it is possible that attenuation of VTA GABA inhibitory neuron may
allow the VTA DA cell of depressive subjects to return to the baseline high fre-
quency firing following rebound sleep as observed in social defeat stress susceptible
mice. As mentioned previously, VTA DA neurons play a key role in modulating
depression-related behaviours (Krishnan et al. 2007; Chaudhury et al. 2013; Cao
et al. 2010; Friedman et al. 2014) and it is likely that aberrations in clock gene
expression in the VTA may play a role in depression-related behaviours.
Manipulation of Clock gene expression in the VTA modulates circadian rhythms,
VTA neural activity and the depressive phenotype (Mukherjee et al. 2010).
Previous work had shown that Clock-mutant mice exhibit increased preference for
cocaine and increased activity in VTA DA cells (Benca et al. 2009) Furthermore,
rescued expression of CLOCK protein via viral mediated gene transfer specifically
in the VTA rescued the behavioural abnormalities (Roybal et al. 2007). These early
findings point to an overlap in the mechanisms by which aberrations in clock gene
function can lead to mood disorders. More recent studies where clock gene
expression was targeted in the VTA alone resulted in altered circadian period an
amplitude suggesting a role of CLOCK in the VTA in regulating circadian rhythms.
Furthermore knock down of the transcription factor CLOCK in VTA DA cells
resulted in changes in expression of a variety of genes which most likely explains
the net increased activity observed in these cells following knock down of clock
gene expression and the consequent functional changes resulting in a mixed state of
mania and depression-like behaviour in these mice (Dupuis et al. 2010). It will be
interesting to determine whether there is a correlation between clock gene regula-
tion and changes in Ih and K+ channels in VTA DA neurons and whether sleep
deprivation induced reversal of depression leads to changes in cellular firing rate via
modulation of various clock genes and associated ion channels. A more recent
study extended the role of clock gene and the regulation of anxiety related beha-
viours. Clock mutant mice were found to exhibit rapid mood cycling across the
light-dark cycle such that the Clock mutants exhibited robust manic-like behaviour
compared to wild-type controls when tested in an open field-, forced swim- and
sucrose-preference test during the day (Sidor et al. 2015). Furthermore,
Clock mutant mice exhibited robust increases in both daytime tyrosine hydroxylase
expression and VTA DA neuron activity (Sidor et al. 2015). Moreover, further
evidence that the molecular components of the circadian timing system have a
critical role in mood regulation comes from numerous findings that mutations of
clock genes Bmal1 and Per2 induce mania-like behaviours in mice while knock-out
of Cryptochrome 1 and 2 genes induces altered anxiety-like behaviours (Hampp
et al. 2008; Kondratova et al. 2010; De Bundel et al. 2013). The circadian nuclear
receptor REV-ERBa, an important constituent of molecular circadian signaling that
serves as transcriptional repressors of the Bmal RNA, has recently been shown to
negatively regulate midbrain DA neuronal function via circadian modulation of
tyrosine hydroxylase mRNA transcription (Chung et al. 2014). REV-ERBa
knockout mice exhibit altered circadian rhythmicity in mood related behaviours
while conditional inhibition of REV-ERBa produces mania-like behaviour (Chung
et al. 2014). The ascending arousal system contains two branches consisting of
discrete cell populations and neurotransmitters (Saper et al. 2005). One branch
consists of the cholinergic projections from the PPTg/LDTg in the brain stem and
basal forebrain. These cholinergic projections, that innervate the thalamus, acti-
vating relay neurons and reticular nuclei essential for thalamocortical transmission,
are most active during wakefulness and REM sleep (Saper et al. 2001; Saper et al.
2010). Both the PPTg and LDTg innervate VTA DA cells, such that the PPTg sends
glutamatergic-cholinergic neurons to the VTA and is able to drive burst (phasic)
firing activity in VTA DA cells, while the cholinergic projection from the LDTg to
VTA DA cells provides the permissive gate that allows VTA DA cells to respond to
glutamatergic input from the PPTg and possible other glutamatergic inputs from the
mPFC and lateral pre-optic-rostral hypothalamic area (Grace et al. 2007; Geisler
and Zahm 2005). The previous findings that VTA DA neuron activity can encode
for the depressive phenotype and that PPTg/LDTg can modulate VTA DA activity
suggest a possible mechanism by which sleep deprivation may alleviate depressive
symptoms. The high activity of PPTg/LDTg during SD by keeping patients awake
may lead to increased phasic VTA DA activity and induce the sensation of reward
while decreasing the depressive episode. This possible mechanism is supported by
findings that activation of LDTg projections to VTA promotes conditioned place
preference and thus encodes rewarding behaviour (Shinohara et al. 2014). It should
be noted however that this mechanism is not as clear cut since we had earlier
described that VTA DA cell neural dynamics appear to have a complex role in
encoding for the depressive phenotype where in some studies robust extreme
stressful paradigms induces phasic firing that leads to encoding of the depressive
phenotype (Chaudhury et al. 2013), while chronic weaker stress paradigms induces
decreased VTA DA activity leading to encoding of the depressive phenotype (Tye
et al. 2013). A systematic study to determine the functional role of PPTg/LDTg on
micro-circuit modulation of VTA DA cell during strong and weak stressors at
different time of the sleep-wake cycle may help alleviate its role as a potential target
of SD induced reversal of depression. A second branch of the ascending arousal
system consists of projections from a number of monoaminergic cell populations
such as the norepinephric neurons of the LC, the serotoninergic neurons of Dorsal
and Medial Raphe, neurons of the periaqueductal grey matter and the histaminergic
neurons in the TMN (Saper et al. 2010). These monoaminergic nuclei are most
active during the wake cycle and quietest during NREM sleep (Fuller et al. 2006;
Aston-Jones and Bloom 1981; Steininger et al. 1999) and send projections to the
lateral hypothalamus, basal forebrain and cerebral cortex (Saper et al. 2001; Jones
2003; Saper 1985). In light of the role of the LH, basal forebrain and cortex in mood
regulation, understanding changes in these neural circuits regulating the wake cycle
may help us to better understand changes in sleep-wake cycle and depression.
A number of these wake promoting nuclei are linked to the VTA DA system. For
example the DR and VTA are reciprocally interconnected (Saper et al. 2001).
Selective lesion of DA in VTA leads to decreased firing of 5-HT neurons in DR
(Guiard et al. 2008). Thus this suggests that DA excite 5-HT cells in DR.
Furthermore selective lesion of 5-HT neurons in DR leads to increased activity in
36 % of VTA DA neurons suggesting that 5-HT neurons inhibit VTA DA neurons.
Classical monoamine antidepressants attenuate the reuptake dynamics of 5-HT
resulting in the alleviation of depressive symptoms by increasing the net effect of
5-HT on cells. A hypothesis by which SD may alleviate depression could be that
prolonged wakefulness leads to increased accumulation of 5-HT. The findings that
selective serotonin reuptake inhibitor (SSRI) escitalopram decreased firing activity
of VTA DA cells while the SSRI citalopram decreased burst firing only in VTA
cells (Dremencov 2009) provide further evidence for the role of VTA DA and DR
5-HT in depression. Apart from reciprocal modulation between VTA DA and DR
5-HT cells, recent evidence has highlighted a role for DR DA cells in modulating
social behaviours. The DR is made of heterogenous nuclei of serotonergic neurons,
as well as neurons that express GABA, Glutamate and Dopamine (Vasudeva et al.
2011). The functional role of DR DA neurons is not well known as it was shown
that DA neurons are not involved in rewarding behaviours such as intracranial
self-stimulation studies (McDevitt et al. 2014). A recent study indicates that DR DA
cells play a role in encoding for an animals experience of social isolation (Nieh
et al. 2016). Specifically this study showed that social isolation induced synaptic
potentiation of glutamatergic inputs onto DR DA cells and that optogenetic stim-
ulation of DR DA cells increased motivation for social preference, in previously
socially isolated mice. However, surprisingly optogenetic induction of these neu-
rons also induced place avoidance (Nieh et al. 2016). It has been hypothesized by
the authors that DR DA neurons in this pathway does not encode for the rewarding
phenomenon of social interaction, as observed in VTA DA cells (Gunaydin et al.
2014; Tsai et al. 2009) but rather modulates a “loneliness-like” state that regulates
social motivation. Furthermore, neural circuit analysis of DR DA projections have
shown that: (a) these neurons innervate the Bed nucleus of the Stria Terminalis
(BNST) and Central amygdala, two regions associated with anxiety and aversive
emotional states (Pellaprat et al. 2014) and (b) these neurons also co-release glu-
tamate which may explain in part the complex and differential effects of DR DA
neurons activity on social preference but not in the rewarding component. Though
the “lonelines” is a difficult concept to test in mice, these findings implicate a role of
the DR DA neurons in encoding for social behaviour which is affected in mood
disorders. Social isolation, social exclusion or feelings of social disconnection can
lead to loneliness which is a strong aversive emotional state in humans and detri-
mental to physical and mental well-being (Cacioppo et al. 2006; Holt-Lunstad et al.
2010; House et al. 1988). It would be interesting to determine whether the DR DA
neurons play a role in wake states and how these may affect social preference.
Depressed patients exhibit changes in sleep regulation in part due to hyperex-
citability and disregulation of the hypothalamus-adrenal (HPA) axis, causing
increased 24-h cortisol secretion due to increased corticotriphin releasing factor
(CRF) production in the paraventricular nucleus of the hypothalamus (Hemmeter
et al. 2010; Holsboer 2000). Conversely, CRF-antagonist has been used to treat
depression and anxiety. Previous studies have shown that increased BDNF release
from VTA DA cells projecting to the NAc (mesolimbic reward pathway) encodes
for the depressive phenotype in mice susceptible to social defeat stress (Krishnan
et al. 2007; Chaudhury et al. 2013; Berton et al. 2006). Furthermore, CRF acti-
vation in the NAc gates VTA DA BDNF release onto post-synaptic neurons
encoding for the depressive phenotype (Walsh et al. 2014a). Therefore an under-
standing of the role of stress on sleep via the HPA axis and its effects on BDNF
signaling in VTA DA neurons may lead to a better understanding of the effects of
stress on sleep modulating mood disorders. BDNF is synthesized as prepro BDNF,
which is then cleaved to form Pre-BDNF to be cleaved further to make BNDNF.
Recent work suggests that pro-BDNF is secreted in activity-dependent manner
along with the enzyme tissue plasminogen activator, which cleaves pro-BDNF to
BDNF (Waterhouse and Xu 2009). Evidence also suggests that pro BDNF and
BDNF activate different intracellular pathways, where pro-BDNF activates low
affinity neurotrophin receptor 75 that is thought to be involved in apoptosis (Roux
and Barker 2002; Lessmann et al. 2003). BNDF on the other hand activates tro-
pomyosin related kinase B (TrkB) receptors where binding of BDNF to TrkB
induces dimerization of receptors leading to autophosphorylation and attenuation of
NMDA receptor currents and the subsequent activation of at least possible different
intracellular pathways. The first pathway regulates activity of PLCy leading to PKC
activation, the second pathway involves modulation of phosphatidyl inositol
3-kinase (PI3K) pathway leading to activation of serine/threonine kinase AKT and
the third pathway involves modulation of mitogen-activated protein kinase (MAPK
aka ERK) which leads to activation of several downstream activators. Activation of
these different pathways leads to different functions in the cell (Mattson 2008;
Yoshii and Constantine-Paton 2010). In general, the PLCy pathway induced release
of intracellular Ca2+ leading to rapid synaptic and ion channel effects while PI3k
and MAPK pathway activation leads to longer lasting effects with a slower tem-
poral dynamics. BDNF is able to directly activate voltage gated sodium channels
leading to rapid depolarization of target neurons (Blum et al. 2002). Changes in
expression of BDNF have been observed in both human depressed patients and
animal models of depression. Human and animal studies have found depression
related decrease in BDNF levels in the hippocampus and prefrontal cortex
(Pellaprat et al. 2014). Since one of the main functions of BDNF is neurogenesis
where it regulates neuronal differentiation and growth (Benraiss et al. 2001; Pencea
et al. 2001), it is therefore not surprising that MDD leads to a corresponding
decrease in hippocampal and prefrontal cortical volume in patients (Bremner et al.
2000; Dwivedi et al. 2003; Castren 2004; Pandey et al. 2008). Not all regions of the
brain exhibit the same form of BDNF signaling during depression. For example,
human and animal studies show that depression leads to increased BDNF signaling
from VTA DA cell projections to the NAc (Krishnan et al. 2007; Berton and Nestler
2006) and in the amygdala (Pellaprat et al. 2014). Furthermore, the increased
BDNF in the amygdala is correlated with the observed hypertrophy in this region in
depressed patients (van Elst 2000; Frodl et al. 2002). Increased BDNF in the NAc
has been well established in the chronic social defeat paradigm of stress where
increased activity of VTA DA cells projecting to the NAc has been shown to be
related to increased BDNF levels in NAc (Krishnan et al. 2007). BDNF was shown
to be synthesized in the VTA and transported down and released from VTA DA
terminals in the NAc (Krishnan et al. 2007). Furthermore, it was shown that CRF
activity either into presynaptic VTA DA terminal in the NAc or acting on
NAc MSN neurons gated the effect of BDNF on encoding for susceptibility to
social defeat stress (Walsh et al. 2014a). Furthermore, in VTA DA cell projections
to amygdala, it is however, unclear whether the BDNF increase in the amygdala is
from the VTA or whether it is produced locally in the amygdala following stress
exposure (Autry and Monteggia 2012). The different effects of BDNF in the neural
circuitry related to depression may arise from a variety of factors. For example, as
mentioned above, Pre-BDNF and BDNF both have effects on cells and they interact
with different receptors that lead to activation of different pathways in target cells. It
would be interesting to determine whether pro-BDNF is co-released from VTA DA
cells onto NAc MSN during during stress exposure in the chronic social defeat
paradigm. Activation of neurotrophin receptor 75 can cause cell death or change
synaptic transmission and axonal elongation. It is possible that high frequency
bursting activity of VTA DA inputs to NAc could lead to increased pro-BDNF
release, which upon activation of neurotrophin receptor 75 on NAc MSN’s, leads to
cell death or change in normal synaptic transmission. In addition, BDNF itself may
be activating different pathways in weighted effects on the PI3K, MAPK and PLCy
pathways in different circuits. Furthermore, differences in neural circuit connec-
tivity may play a role in the effects of BDNF on depression. As mentioned pre-
viously, BNDF input from the VTA DA cells onto NAC is gated via the stress
factor CRF, Likewise the amygdala receives input from the HPA axis that may play
a role in gating increased BDNF levels in depression, while a differential input to
mPFC and hippocampus may lead to decreased BDNF in encoding for the
depressive phenotype. Finally another possible and potential reason for the differ-
ential role of BDNF in these regions may be related to their potential differential
regulation by the circadian and sleep-wake systems of the brain. Transcriptional
studies show that genes that encode for proteins related to plasticity such as BDNF
are upregulated during wakefulness and down regulated during sleep (Gronli et al.
2013; Elliott et al. 2014; Tononi and Cirelli 2001; Porkka-Heiskanen 2003). It has
been shown that short term SD upregulates BDNF expression in some brain regions
(Cirelli and Tononi 2000; Fujihara et al. 2003; Guzman-Marin et al. 2006; Hairston
et al. 2004; Taishi et al. 2001). Therefore, a possible molecular mechanism for the
effect of SD on alleviating depressive symptoms is through induction of BDNF
release in regions such as the hippocampus and PFC while the simultaneous 5-HT
release from DR neurons onto VTA DA cells may ™decrease VTA DA neuronal
activity leading to decreased phasic VTA input to NAc and consequent decreased
BDNF release.
9 Conclusion
Dopamine is produced in a relatively small number of regions of the brain though

the dopaminergic neurons project to wide areas of the brain where they regulate
aspects of behaviours ranging from cognition, motivation, reward, movement
control, learning and memory. Furthermore, aberrations in brain dopamine sig-
naling have been implicated in a variety of disorders such as Parkinsonism,
Schizophrenia, addiction and more recently mood disorders such as depression.
Accumulating evidence indicates that mood disorder is a neural circuit disorder as
evidenced by findings from both basic and deep-brain stimulation (DBS), clinical
studies.
Patients with depression typically exhibit abnormal circadian and sleep-wake
patterns, though it remains unclear whether aberrations in circadian and sleep-wake
patterns are the cause or consequence of depression. The circadian and sleep-wake
rhythms are separate but closely linked systems and growing evidence shows from
neural circuit studies that these regions have close connection with regions of the
brain associated with mood disorders.
In our chapter, we have focused our main discussion on the role of dopamine
and other neurotransmitters in encoding for depression and attempt to highlight
some of the evidence of how the dopamine signaling, primarily, in the reward
pathway of the brain is linked to the circadian and sleep-wake rhythms. By high-
lighting the neural circuits together with cellular and molecular dynamics linking
these rhythmic processes with dopamine signaling we hope to develop a better
understanding of how changes in these systems can lead to depression.
Understanding these mechanisms that lead to depression has the great potential to
ultimately lead to the future development of rapidly acting antidepressant therapies.
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Depression, Sleep Disorders, and DA
Traci J. Speed and Patrick H. Finan
And yet in certain of these cases there is mere anger and grief
and sad dejection of mind…they are suspicious of poisoning or
flee to the desert from misanthropy or turn suspicious or
contract a hatred of life. Or if at any time a relaxation takes
place, in most cases hilarity supervenes. The individuals are
dull or stern, dejected or unreasonably torpid…they also
become peevish, dispirited and start up from a disturbed sleep.
—Arateus (from: Taylor and Fink 2006)
Abstract Sleep is the quintessential circadian behavior, driven by homeostatic and

environmental forces, and essential for survival. Disruption of circadian rhythms
leads to numerous metabolic, cardiovascular, and neuropsychiatric diseases.
Depression displays its own rhythmic pattern with recurrent episodes frequently
driven by environmental cues including poor sleep. Insomnia, defined as difficulty
initiating or maintaining sleep or non-restorative sleep that causes significant
daytime impairment, affects the majority of individuals with depression. Insomnia
symptoms frequently persist even after remission from affective disturbances and
are significant risk factors for recurrence and poor clinical outcomes. Research has
demonstrated a bidirectional and longitudinal risk relationship between insomnia
and depressive disorders, however the exact mechanisms underlying these associ-
ations remain unknown. The evidence implicates dopamine as a neurobiological
factor associated with symptoms of insomnia and depression. Dopamine is a
neuromodulator that regulates reward processing, arousal states, affect, and mood
regulation. However, the putative role of dopamine in insomnia and depression has
largely been underappreciated and understudied. Indeed, elucidating the common
dopaminergic pathways linking mood and sleep disorders may shed light on the
development and progression of common symptoms of both disorders and provide
targets for interventions. It is reasonable to glean from this chapter that a common
alteration in mesolimbic dopaminergic signaling pathway underlies the comorbidity
of depression, insomnia, and circadian rhythm disorders. In the present chapter, our
goals are to (a) provide a brief overview of the role of dopamine in sleep and wake,
with a focus on sleep architecture; (b) describe the role of dopamine in depression;
(c) discuss the possible implications of sleep architecture-mediated dopaminergic
T.J. Speed (&) P.H. Finan

Department of Psychiatry and Behavioral Sciences,
Johns Hopkins University School of Medicine, Baltimore, USA
e-mail: tspeed1@jhmi.edu

DOI 10.1007/978-3-319-46437-4_9
192 T.J. Speed and P.H. Finan
changes for depression, and (d) discuss the possible implications of

circadian-mediated dopaminergic changes for depression.

Keywords Dopamine Depression Mood disorders Insomnia Circadian

rhythm Anhedonia Reward processing
The connection between depression and sleep has been described since antiquity.
Insomnia—a chronic sleep disorder characterized by difficulty initiating and/or
maintaining sleep—is such a fundamental feature of depression that some have
argued major depressive disorder (MDD) should not be diagnosed in the absence of
sleep disturbances (Jindal and Thase 2004; Nutt et al. 2008). Sleep is the
quintessential circadian behavior, driven by homeostatic and environmental forces,
and essential for survival. Disruption of circadian rhythms leads to numerous
metabolic, cardiovascular, and neuropsychiatric diseases and is a risk factor for
mortality (Yaggi et al. 2006; Cappuccio et al. 2010; Hoevenaar-Blom et al. 2011;
Landgraf et al. 2014; Zuurbier et al. 2015; Barandas et al. 2015).
Depression displays its own rhythmic pattern with recurrent episodes frequently
driven by environmental cues such as changes of season, dark-light patterns, and
hormonal fluctuations. Insomnia, defined as difficulty initiating or maintaining sleep
or non-restorative sleep that causes significant daytime impairment, affects nearly
80 % of individuals with depression (Tsuno et al. 2005; Yates et al. 2007).
Insomnia symptoms frequently persist even after remission from affective distur-
bances and are significant risk factors for recurrence (Nierenberg et al. 2010;
Baglioni et al. 2011). Additionally, depressed individuals with symptoms of
insomnia have worse clinical outcomes, attrition rates, and response to treatment
compared with good sleepers (Smith et al. 2005). Sleep disturbances are a common
prodromal symptom for depressive episodes and interepisode sleep symptoms are
correlated with future depressive episodes (Perlis et al. 1997; Jackson et al. 2003;
Eidelman et al. 2010; Kaplan et al. 2014).
While the association between sleep and depression has been noted for centuries,
it is only within the past few decades that work began in earnest to elucidate the
molecular mechanisms underlying the comorbidity of sleep disturbances and
depression. Half a century ago the monoamine hypothesis emerged, suggesting that
depletion of monoamines, particularly serotonin and norepinephrine, forms the
pathophysiological basis of depression (Hillhouse and Porter 2015). This led to the
development of our current pharmacological treatments, which act to block reup-
take or inhibit degradation of serotonin and/or norepinephrine at the synaptic cleft
and increase their transmission. However, clinical observations and epidemiological
studies reveal that there is a delayed onset before remission of depressive symptoms
is achieved, remission rates are low, and residual symptoms often remain. Insomnia
is one of the most prevalent residual symptoms, suggesting that the first line
treatments do not adequately address the interaction between sleep and mood
(Ohayon and Roth 2003; Manglick et al. 2013).
Depression, Sleep Disorders, and DA 193
Dopaminergic (DAergic) pathways in the brain are abundant, site specific, and
integral to affect, mood, motivation, and sleep. However, DAergic agents are not
first line treatments for mood disorders. In a recent theoretical review, Finan and
Smith posited that the pattern of DAergic changes observed under conditions of
sleep loss and depression was suggestive of a common pathophysiology whereby
elevations in tonic DA levels promote wake and, by virtue of inhibiting phasic
DAergic burst firing, promote anhedonic emotional states and behaviors (Finan and
Smith 2013). A comprehensive review of the role of DA in sleep and wake is
presented elsewhere in this volume. In the present chapter, our goals are to
(a) provide a brief overview of the role of DA in sleep and wake, with a focus on
sleep architecture; (b) describe the role of DA in depression; (c) discuss the possible
implications of sleep architecture-mediated DAergic changes for depression, and
(d) discuss the possible implications of circadian-mediated DAergic changes for
depression.
1 DA, Sleep Architecture, and Depression
1.1 DA and Sleep Architecture
The sleep-wake cycle is centrally regulated by the interaction between sleep pro-
moting neurons in the hypothalamus and basal forebrain and wake promoting
neurons in the hypothalamus and brainstem (Schwartz and Roth 2008). DAergic
neurons are localized to specific regions of the brain including structures relevant to
the sleep-wake cycle. For example, DA receptors are abundant in key structures of
the ascending reticular activating system, including the dorsal and median raphe
nuclei and the ventral periaqueductal gray, which are critical in modulating sleep
(Bannon et al. 1983; Lu et al. 2006; Monti and Monti 2007).
The sleep-wake cycle is characterized by variations in electroencephalogram
(EEG) patterns, eye movements, and muscle tone. Human sleep is divided into two
broad categories, identified by the presence or absence of rapid eye movement
(REM). Non-REM (NREM) sleep is the period of rest and energy conservation
when physiological processes slow down, including respiration, blood pressure, and
heart rate. In NREM, eyes move slowly, if at all, and muscles are relaxed. NREM
sleep is made of 3 stages of progressively deeper sleep. Frequency of electrical
waves decreases among NREM stages 1–3 while the energy discharged at each
impulse increases. REM follows a complete cycle of these stages and is marked by
intense mental activity. In REM, dreaming occurs, cerebral metabolism is rapid and
diffuse, and large muscles are essentially paralyzed. REM sleep primarily takes
place toward the end of the night. In healthy individuals, slow-wave sleep pre-
dominates during the first part of the night when the need for sleep is high. Slow
wave activity diminishes throughout the sleep cycle as sleep debt is made up and
sleep drive is decreased.
Mice lacking the DA transporter gene show increased wakefulness and less
NREM sleep in a 24 h period, and in these knockouts, neither modafinil nor
amphetamines promote increased wakefulness (Wisor et al. 2001). Similarly,
knockout mice missing a key enzymatic precursor in DA metabolism, DA beta
hydroxylase, have increased total sleep and reduced latency to sleep after mild
stressors (Hunsley and Palmiter 2003). These studies suggest that adaptive DA
clearing is essential for normative progression through the sleep stages.
In rodent studies, systemic administration of DA receptor agonists increases time
spent awake and reduces both slow wave (i.e., stage NREM 3) and REM sleep
(Andersen et al. 2009). Comparatively, systemic administration of DA receptor
antagonists increases slow wave and REM sleep, and reduces time spent awake
(Trampus et al. 1990; Monti et al. 1990). DAergic effects on sleep and wake appear
to be dose-dependent and receptor-specific. For instance, low doses of D2 receptor
agonists induce sedation, possibly due to activation of presynaptic autoreceptors,
whereas higher doses of D2-specific agonists promote waking (Monti et al. 1989;
Python et al. 1996; Olive et al. 1998). However, comparable to amphetamine-like
stimulants or higher doses of D2 agonists, locomotor activities and motor stereo-
typies are not observed with lower doses of D1 agonists suggesting dose and
receptor-specific DAergic effects (Isaac and Berridge 2003).
EEG patterns change predictably from the slow waves and spindles of NREM to
the low voltage, fast activity of waking and REM. In almost all animals, sleep is
characterized by quiescence and increased arousal threshold. Increased arousal
threshold is most important in distinguishing sleep from rest, which suggests that
the reduced ability to respond to the environment is a requirement for the restorative
function of sleep (Cirelli and Tononi 2008). Despite evidence that DA plays a role
in arousal, the interaction of sleep architecture and DA has long been understudied.
This may be attributable to the results from early neurophysiological studies
demonstrating that DAergic cells in the ventral tegmental area (VTA) and sub-
stantia nigra pars compacta did not display robust alterations in their firing rate
across the sleep-wake cycle (Trulson et al. 1981; Steinfels et al. 1983; Trulson and
Preussler 1984). Conversely, early studies demonstrated higher discharge rates of
serotonergic and noradrenergic neurons during wake relative to slow-wave sleep
(Vanderwolf 1988; Gillin et al. 1993). It is notable that despite invariability of DA
neuronal firing rate across sleep-wake state, in vivo electrophysiological studies
demonstrate fluctuations in post-synaptic release of DA in the caudate nucleus
across sleep-wake state (Trulson 1985). Indeed, converging evidence suggests that
increased extracellular DA levels occur with increased bursting activity indepen-
dent of the mean firing rate (Floresco et al. 2003). Additionally, evidence indicates
an increased burst firing activity of DA neurons during wake and REM stages with
simultaneous enhanced release of DA in the VTA and nucleus accumbens (NAcc)
(Léna et al. 2005). Electrophysiological studies in rats demonstrate that DAergic
neurons exhibit tonic irregular spike firing modulated by bursts of spikes of
decreasing spike amplitude and a brief silence during NREM stages. The DA firing
rate appears to be variable in NREM, the importance of which is underscored by
shifts in discharge pattern resulting in larger extracellular DA accumulation (Dahan

et al. 2007).
These studies guide our understanding of DAergic signaling across the
sleep-wake cycle and suggest that DA plays a critical role in arousal from
sleep. Furthermore, they suggest that alterations in DAergic neurotransmission may
influence the progression through sleep stages, thereby influencing the quality of
one’s sleep. Finally, they suggest that DA release and firing rates appear to vary
across sleep stages. Taken together, these data indicate that there may be a recip-
rocal relationship between DA neurotransmission and sleep architecture, whereby
changes in the amount of NREM and/or REM sleep achieved will result in different
patterns of DA release that predominate, and changes in overall DA tone will
influence the extent of NREM and REM sleep achieved.
1.2 DA and Depression
DA was implicated in the etiology of MDD from observations that reserpine, which
reduces DA levels, induced depressed mood (Lion et al. 1975). Conversely, cocaine
and amphetamine, which increase DA levels, elevated mood (Coppen 1967).
However, studies investigating the role of DA in the pathophysiology of MDD have
been limited since the emergence of selective serotonin- and
serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs) as first-line
antidepressant treatment. Animal models have provided the most consistent evi-
dence for a role of DA in depressive phenotypes. Animals exhibiting learned
helplessness, a model of depressive-like behavior, show DA depletion in the cau-
date nucleus and NAcc (Anisman et al. 1979). Several clinically effective antide-
pressants produce reduced immobility in the rodent forced swim test, as evidenced
by studies involving tricyclic antidepressants, the DA reuptake inhibitor nomi-
fensine, and D2/D3 agonists (Basso et al. 2005). Compared to mice knockout
studies of the serotonin and norepinephrine transporter proteins, the effects of DAT
knockout produced greater changes in behavior sensitive to antidepressant-like
phenotypes, providing further evidence that DA may have a greater effects on MDD
pathophysiology than previously appreciated (Perona et al. 2008).
Studies of DA concentrations and receptor density in humans have been less
definitive. Evidence from postmortem studies in MDD is limited and complicated
by inclusion of victims of suicide (which is not pathognomonic for MDD), as well
as presence of psychotropic medications in many studies (Pare et al. 1969; Arranz
et al. 1997; Bowden et al. 1997a, b, c). However, one elegant postmortem study of
depressed individuals showed reduced DAT density and elevated D2/D3 receptor
binding in central and basal nuclei of the amygdala compared with healthy controls
(Klimek et al. 2002). Classical studies of cerebrospinal fluid (CSF) levels of
monoamines have demonstrated lower concentrations of homovanillic acid (HVA),
the major metabolite of DA, in depressed individuals compared to healthy controls
(Traskman et al. 1981; Asberg et al. 1984), suggestive of altered DA functions in
the CNS. While CSF HVA levels are not an effective biomarker to predict
antidepressant treatment response, numerous studies have demonstrated that
treatment-resistant depressed patients have significantly higher CSF concentrations
following ECT treatment (Rudorfer et al. 1991a, b; Mathe 1999; Nikisch and Mathe
2008). Taken together these studies suggest that reduced DAergic neurotransmis-
sion is involved in the pathophysiology of MDD.
Mounting evidence suggests that the depressive symptom complex known as
anhedonia is especially linked to DA neurotransmission. Anhedonia is the loss of
interest in or reduced pleasure from rewarding activities, and is a key feature of
MDD. There is growing interest in understanding reward processing in neuropsy-
chiatric disorders, as anhedonic symptoms appear to be more common than origi-
nally reported, negatively impact long-term functional outcomes, and increase risk
of mortality (Treadway and Zald 2011; Vrieze et al. 2013b). In a retrospective
meta-analysis of 811 adults with moderate to severe depression, symptoms of
anhedonia including loss of interest, diminished activity, and inability to make
decisions all predicted poor depression outcomes, even after adjusting for overall
depression severity and other covariates (Uher et al. 2011).
Anhedonia is robustly linked to dysfunction within the mesolimbic reward
pathway (Wise 2008). The reward pathway is a complex circuitry housed within the
limbic system. Our understanding of alterations in the reward pathway in neu-
ropsychiatric disorders such as depression comes from extensive studies in animal
models and pathophysiological and neuroimaging studies in humans. Several
neurotransmitters including norepinephrine (NE), oxytocin, serotonin (5-HT),
opioids and endocannabinoids (ECBs) play a role in reward mechanisms and are
beyond the scope of this chapter (Eppinger et al. 2011; Faulkner and Deakin 2014;
Proulx et al. 2014). DA is arguably the most well-known excitatory component of
behavioral reward signaling. Reward processing relies on a complex interaction of
signals across the brain coordinated in part by the hippocampus and the striatum,
which includes dorsal and ventral segments (Haber and Knutson 2009). The dorsal
striatum, thought to be the site of stimulus-directed behaviors, contains the caudate
nucleus and putamen. The ventral striatum houses the NAcc, and is thought to be
the site of goal-directed behaviors (Da Cunha et al. 2012). DAergic neurons project
from the brainstem into the striatum; mesolimbic DA projections arise from the
VTA and signal to the NAcc, and nigrostriatal DA projections arise from the
substantia nigra (SN) and signal to the dorsal striatum. Also of importance in
reward processing are the mesocortical DA projections, which arise from the VTA
and signal the prefrontal cortex (PFC) (Lammel et al. 2014). Reward processing is
under regulatory control from both glutamatergic projections, arising from the PFC,
amygdala and hippocampus, and GABAnergic projections in the brainstem via the
NAcc and the ventral pallidum (Nestler and Carlezon 2006; Heshmati and Russo
2015).
Clinically, individuals with anhedonic MDD demonstrate decreased motivation
to engage in goal-directed behaviors. Under controlled experimental settings,
researchers have demonstrated that diminished interest or pleasure is a function of
attenuated reward responsiveness (Der-Avakian and Markou 2012). Individuals
with anhedonic depression have reduced ability to modulate behavior as function of

reward. Compared with healthy controls, individuals with MDD have initial deficits
in reward-based learning. Reward learning impairment is highest in individuals
with anhedonic depression and predicts depression chronicity following antide-
pressant treatment (Vrieze et al. 2013a). Depression severity is also associated with
greater inability in developing behavior to maximize reward. DA plays a critical
role in incentive motivation, reward learning and reward response (Berridge 2007;
Schultz 2013) and studies have investigated if altered phasic DAergic signaling
affects reward learning. For example, reward responsiveness was decreased fol-
lowing pharmacologically induced attenuation of phasic DAergic signaling
(Pizzagalli et al. 2008). After a D-amphetamine challenge, depressed subjects
showed a significantly greater behavioral response to its rewarding effects, as well
as altered brain activation of ventrolateral prefrontal cortex, orbitofrontal cortex and
caudate and putamen, assessed through functional neuroimaging. This corroborates
previous studies in which medication-free severely depressed individuals had
greater reward than controls or mildy depressed individuals after oral
d-amphetamine (Tremblay et al. 2005).
Taken together, the data suggest that dysregulation of DA neurotransmission and
reward system function are critical elements of depression.
1.3 Areas of Synergy
In MDD, sleep continuity is impaired and sleep efficiency is reduced (Sutton 2014).
In terms of sleep architecture, REM latency is shortened, the duration of first REM
period is increased, and slow wave sleep is decreased among patients with
depression compared to controls (Thase et al. 1998). Furthermore, slow wave sleep
that normally occurs during this first non-REM period tends to shift into the second
non-REM period in patients with depression (Armitage et al. 2007). REM is dis-
tributed differently in depression, and has a greater distribution earlier in sleep cycle
(Paykel 2008). There is also evidence that shortened REM latency persists after
remission from an acute depressive episode (Giles et al. 1993; Tsuno et al. 2005).
As we have discussed, insomnia and depression are commonly comorbid.
Understanding the bidirectional association between sleep and depression and the
influence sleep disruption has on the trajectory of depression is essential for opti-
mizing treatment strategies for depression. An emerging view that insomnia is
comorbid with depression, rather than simply a symptom of depression warrants
treatment strategies which target both insomnia and depression. Disruption of
DAergic pathways in mesolimbic brain regions is implicated in the pathophysiol-
ogy of mood dysregulation and sleep disruption. Indeed, elucidating the common
DAergic pathways linking mood and sleep disorders may shed light on the
development and progression of common symptoms of both disorders and provide
targets for pharmacological interventions. Furthermore, nonpharmacological inter-
ventions for the treatment of insomnia and depression may reduce common
symptoms and prevent relapse. We turn here to the link between circadian rhythm
and depression.
2 DA, Circadian Rhythms, and Depression
2.1 DA and Circadian Rhythms
The sleep-wake cycle is regulated by two separate but interacting processes—sleep

homeostasis and circadian rhythms (Cirelli 2009). Sleep homeostasis is dependent
on wakefulness (i.e., increased time awake increases the drive to sleep). Sleep
homeostasis and circadian processes work in concert to facilitate consolidated
nighttime sleep in humans. In healthy sleepers, the drive to remain awake from the
circadian clock and the homeostatic drive to sleep are synchronized at approxi-
mately 11 P.M. Sleep abnormalities can arise from disruption to either the home-
ostatic sleep drive to sleep or circadian process (Schwartz and Roth 2008).
The circadian process regulates daily rhythms of the body and brain independent
of sleep. The suprachiasmatic nucleus (SCN) is known as the circadian pacemaker.
The pacemaker is set to a 24 h period based on the Earth’s rotation and kept in
phase with seasonally shifting day length through a process called entrainment.
Zeitgebers are environmental cues that support entrainment. Light is the principle
zeitgeber. Light activates SCN gene activity resulting in daily resetting of the
circadian clock, a process which allows for adaptability of the circadian oscillations
such that the endogenous SCN circadian oscillation becomes equal to that of the
light/dark cycle (Welsh et al. 2010). The SCN maintains synchronized physiolog-
ical processes in peripheral tissues through efferent projections to the autonomic
nervous system and hypothalamic-pituitary axis thus controlling body temperature,
endocrine signaling, and behaviors (Dibner et al. 2010).
A molecular oscillator mechanism is found in most cells throughout the body.
The circadian system comprises a network of synchronized cell-autonomous 24-h
oscillators that fine tune physiology and behavior to the variations of the envi-
ronmental day. Evolving research over the past century has demonstrated that most
key physiological functions including sleep-wake cycle, heart rate, blood pressure,
body temperature, hormone fluctuations, metabolism, and even cellular processes
including transcription and translation oscillate in a 24-h period (Ueda 2002;
Duffield 2003; Albrecht 2012). If signals necessary for entrainment of central and
peripheral oscillators are uncoupled, clocks in different tissues become desyn-
chronized, resulting in internal desynchrony, as experienced in jet lag (Vosko et al.
2010).
Given the ubiquity of circadian processes across organ systems, it is perhaps
not surprising that DA is under circadian regulation. For example, microdialysis
studies in rodent models have found that DA levels in the prefrontal cortex and
NAcc exhibit a diurnal rhythm. Prior research studies of circadian oscillation in
Xenopus laevis demonstrated that both light and DA are able to phase shift the
retinal melatonin rhythm (Cahill and Besharse 1991). D2-like receptor activation
causes a decrease in cAMP levels (Vallone et al. 2000). Increasing cAMP in
Xenopus retina blocks DAergic-induced phase shifting, but not light-mediated
phase shifting (Hasegawa and Cahill 1999). Thus, light and DA cause phase
shifts via different second messenger systems (Steenhard and Besharse 2000).
Studies in Drosophila have also suggested that light modulates DAergic sig-
naling. In particular, environmental light suppressed the wake-promoting effects
of DA in fly brains via upregulation of inhibitory DA receptors (Shang et al.
2011).
Additional animal studies have demonstrated that hypothalamic DAergic neu-
rons are involved in light-dependent changes in affective states and furthermore that
photoperiodic changes in DA metabolism in the hypothalamus occur in species
with seasonal breeding patterns (Benson 1987; Deats et al. 2015). For instance,
differences in effect size and direction of DA levels in response to photoperiod
changes varies in chipmunks and mice (Goda et al. 2015). Additionally, micro-
dialysis studies of DA concentrations in rat models demonstrate that during the light
period, when rats typically sleep, extracellular DA levels in the striatum and pre-
frontal cortex are lower than during the dark period (Smith et al. 1992; Feenstra
et al. 2000). Taken together, these observations support the hypothesis that DA
neurotransmission is regulated by light, albeit in an apparent species-specific
fashion.
2.2 Circadian Rhythms and Depression
Genetic and epigenetic studies of clock genes may shed light on the pathophysi-
ology of affective disorders. For instance, mouse models with mutations of the
clock gene result in behavioral changes resembling mania including hyperactivity,
decreased sleep, decreased anxiety to stress, and increased proneness for cocaine
(Roybal 2007). In human studies, polymorphisms in clock genes may have higher
occurrence of affective disorders, although there is no clear association (Lamont
et al. 2007). And individuals who do shift work have been shown to reveal
increased risk of metabolic and psychiatric diseases. Genetic variations have even
been noted in the clock genes, clock and per, for individuals with sleep disorders
and chronotype preferences. Clinically, shift workers have a higher prevalence of
mood disorders, which may represent a response to circadian disruptions presumed
to be due to a molecular clock that is not able to properly adapt to certain types of
environmental or other changes (McClung 2007; Barger et al. 2009).
Links between circadian rhythms and depression were first evidenced in 1960s
when it was discovered that depressive patients lose 24-h rhythmicity in cortisol
secretion, representing abnormal disinhibition of neuroendocrine processes (Sachar
1973). Indeed, blunted or abnormal circadian rhythms in physiological processes
including body temperature, plasma cortisol, norepinephrine, thyroid stimulating

hormone, blood pressure, pulse, and melatonin have been found in individuals with
MDD (McClung 2007). Moreover, circadian rhythms predict the onset of depres-
sion and even precipitate depression or mania in susceptible individuals (Plante and
Winkelman 2008).
Although the sleep/wake cycle is the most familiar circadian cycle, mood,
alertness, and cognitive performance also vary with the time of day (Wright et al.
2012). Mood is generally lower in morning, best towards the evening, and declines
overall with extended wakefulness (Wirz-Justice 2008). Mood instability may in
fact arise from an abnormal phase relationship between circadian and homeostatic
processes (Wulff et al. 2010).
Early theories proposed that mood disorders are characterized by a misalignment
of the endogenous circadian pacemaker with sleep timing (Emens et al. 2009).
Sleep and circadian disruptions associated with mood disorders may be related to
deficiencies in entrainment. Mammals are capable of adapting their activity rhythms
and sleep-wake cycle in response to food and non-photic stimuli (Sollars and
Pickard 2015). Indeed, throughout evolution, organisms have developed behavioral
strategies to accommodate the day-night cycle. In healthy individuals, bright light
in the evening delays the clock and bright light in the morning synchronizes the
clock to a 24-h rhythm. Extremes within either group are examples of phase
advance or phase delay. The inability of circadian clocks to adapt to changes in
seasons, stress-sleep schedules, and time zones is proposed to play a role in mood
dysregulation (McClung 2007). Jetlag, shift work, and social jetlag are predictive of
depressive and manic states (Baron and Reid 2014). Research using various diurnal
and nocturnal rodent species have found that short photoperiods similar to light
exposure during winter months induce depression-related behaviors and hip-
pocampal learning deficits (Einat et al. 2006; Ashkenazy-Frolinger et al. 2010;
Workman et al. 2011).
Delayed circadian sleep phase, also known as eveningness, is associated with
disturbances in reward-related behavior and altered function in reward circuitry in
neuroimaging studies (Hasler and Troxel 2010; Hasler et al. 2013). Both fMRI and
PET imaging studies have shown reduced medial PFC reactivity during reward
anticipation in evening type healthy adolescents (Forbes and Dahl 2012). The
increased prevalence of eveningness during adolescence may be a risk factor for the
emergence of depression and help explain the onset of illness in this age
group. Neuroimaging, polysomnography, and EEG studies in probands of indi-
viduals with MDD have shown that altered circadian rhythms such as tendency
towards eveningness and REM disturbances are risk factors for depression.
Individuals who are able to shift their chronotype from eveningness to morningness
in the context of a behavioral sleep intervention demonstrate reductions in
depression, increases in positive affect, and improvements in sleep quality (Hasler
et al. 2015).
2.3 Areas of Synergy
Recent advances in understanding of the neural and genetic basis of sleep and
circadian rhythm is leading to greater understanding of the relationship of sleep and
mood. Over the past decade it has become clear that the SCN is not the only
circadian oscillator in mammalian systems. With the recent discovery of clock
genes, researchers are finally shedding light on the molecular mechanisms of cir-
cadian rhythms. Almost all circadian oscillators are regulated by a series of positive
and negative feedback mechanisms used to generate 24-h timing circuits
(Bell-Pedersen et al. 2005). Several regions of the brain besides the SCN have the
capacity to generate circadian oscillations and virtually all organs of the body
contain autonomous circadian oscillators (Dibner et al. 2010). The oscillators
outside the SCN use the same core clock genes as the SCN, and 5–10 % of the
transcriptome in peripheral tissues display circadian rhythms (Duffield 2003; Maret
et al. 2007; Barclay et al. 2012).
Given the role of the circadian clock, disruptions of the clock itself or down-
stream components including transcriptional regulation may explain pathological
changes in metabolism and physiology that are associated with sleep disruption.
The period gene has been shown to interact with DA D2/D3 receptors in Drosophila
(Andretic and Hirsh 2000). Discovery that mutations in the period gene modified or
eliminated circadian rhythmicity led to discovery of the core molecular clock genes
(Zheng et al. 1999). Generation of circadian oscillations in the SCN is due to two
interacting feedback loops that either stimulate or inhibit gene
transcription/translation (Bell-Pedersen et al. 2005). Four integrated clock proteins
form the core of the SCN molecular clock. CLOCK and BMAL1 activate PER and
CRY proteins. PER and CRY are negative regulators that repress their own tran-
scription by interacting with the CLOCK:BMAL1 complex. Once PER and CRY
proteins are degraded, repression on CLOCK:BMAL ends and the cycle begins
again (Takahashi et al. 2008). More recent studies have demonstrated that DA
receptor-mediated intracellular signaling differentially regulates neuronal clock
gene expression at the cellular level (Imbesi et al. 2009).
Clock gene mutations have serendipitously provided unexpected models of
mania. Clock mutant mice have mania-like phenotypes including hyperactivity,
decreased sleep, decreased depressive-like behaviors, and increase reward value
(Roybal 2007). Knockdown of the clock gene in the VTA, which gives rise to
DAergic neurons, can replicate these behaviors. Clock may also regulate the
expression of other VTA-specific genes (Sidor et al. 2015). For instance, genes
involved in DA synthesis are altered following clock knockdown (Mukherjee et al.
2010).
Converging evidence suggests that variations in DA availability modulate
affective state, depression, and reward processes (Haber and Knutson 2009; Felten
et al. 2011; Forbes and Dahl 2012). Neuroimaging studies of MDD probands have
demonstrated reduced reward-related ventral striatal activation (Gotlib et al. 2010;
Sharp et al. 2014; Whitton et al. 2015), which is predictive of increased depressive
symptoms in adolescents (Forbes et al. 2007; Morgan et al. 2013). At the same
time, altered circadian rhythms in probands predicts incident mood disorders
(Nurnberger et al. 1988; Ritter et al. 2012; Duffy et al. 2015; Ng et al. 2015).
Taking into account that depression probands have sleep disturbances and reward
disturbances, it seems likely that an exogenous stimulus, such as environmental
cue, or life stressors may further disrupt the system and lead to state of internal
desynchronization, along with disruption of hormonal and behavioral rhythms.
Neuroimaging studies of healthy individuals have demonstrated an association
between seasons and presynaptic striatal DA synthesis (Eisenberg et al. 2010).
Seasonal affective disorder, characterized by depressive symptoms in the winter
months, may arise from a failure to adapt to seasonal changes in the light-dark
cycle. In fact, the most effective treatment for seasonal affective disorder is bright
light therapy, which is hypothesized to advance the circadian clock to coincide with
the sleep-wake cycle.
There appear to be common and overlapping pathways linking circadian rhythm
abnormalities and depression. Both are associated with defects in DA neurotrans-
mission and common DA signaling pathways account for comorbidity of disorders.
However, DA remains a challenging target in the link between sleep and depres-
sion. Although studies in numerous animal species have demonstrated a link
between DA and light, and effects on circadian rhythm (e.g., Hasegawa and Cahill
1999; Steenhard and Besharse 2000; Besharse et al. 2004; Hirsh et al. 2010), we do
not yet have advanced technology to accurately detect changes in DAergic sig-
naling in humans.
Despite limitations in assessing the nuances of DAergic signaling, evidence
implicates a role of altered DAergic signaling in the pathogenesis of both circadian
rhythm disruption and depression. Given the complexity of the mesolimbic
DAergic system, studying the separate and combined effects of altered DAergic
signaling in circadian rhythm disruption and depression may advance our under-
standings of the pathophysiology of these disorders and provide novel therapeutic
targets in the treatment of depression.
3 Conclusions and Future Directions
The evidence implicates DA as a neurobiological factor associated with symptoms

of insomnia and depression. Sleep disturbances are nearly ubiquitous in depression.
Research has demonstrated a bidirectional and longitudinal risk relationship
between insomnia and depressive disorders, however the exact mechanisms
underlying these associations remain unknown. DA is a neuromodulator that reg-
ulates reward processing, arousal states, affect and mood regulation. However, the
putative role of DA in insomnia and depression has largely been underappreciated
and understudied. With advancement in neurophysiological techniques and through
animal and clinical studies of enzymes involved in DAergic signaling, converging
evidence suggests that adaptive DAergic signaling is indeed involved in sleep-wake
states. It is reasonable to glean from this chapter that a common alteration in

mesolimbic DAergic signaling pathway underlies the comorbidity of depression,
insomnia, and circadian rhythm disorders.
It is likely that DAergic influence on insomnia and depression is dependent on
receptor subtype, receptor pharmacokinetics, homeostatic regulation of DA release,
neuroanatomical connectivity, genetic variability, epigenetic modifications, and
interactions with other neurotransmitters. With clinical evidence suggestive that
current pharmacological therapies targeting only serotonergic and noradrenergic
pathways do not adequately treat comorbid depression and insomnia, further
investigation of DA signaling pathways remains a promising target. Rigorous
studies to evaluate the role of altered DAergic function in the association between
sleep and depression provide hope for more efficient and efficacious pharmaco-
logical and nonpharmacological interventions for insomnia and depression.
The current literature does not provide evidence on the temporal dynamics of
DAergic dysregulation in relation to insomnia and depression. A future direction is
to evaluate disruptions in DAergic signaling congruent with alterations in circadian
rhythms, sleep, reward systems, and depression. Prospective studies conducted in
MDD probands, who frequently have altered reward processing, altered circadian
rhythms, and REM disturbances prior to onset of depressive symptoms, may yield
promising results.
Another intriguing step is to understand if altered DAergic signaling is reversible
with nonpharmacological interventions. Neuroimaging studies have found several
brain regions involved in DAergic signaling to be hypermetabolic during NREM in
primary insomnia compared with healthy controls (Nofzinger et al. 2004).
Cognitive behavioral therapy for insomnia is the first line treatment of chronic
insomnia disorder. In addition to improving sleep quality it also reduces depressive
symptoms. The rapid antidepressant effects of sleep deprivation, the benefit of light
therapy in seasonal affective disorders, and the benefits of an imposed sleep
schedule are likely the result of re-aligning circadian and homeostatic processes
(Wirz-Justice and Van den Hoofdakker 1999). It therefore seems promising to
consider alternative molecular targets involved in the sleep-wake cycle.
The mesolimbic DA system is regulated by and connected with numerous
neurophysiological pathways including orexin, glutamate, and
gamma-aminobutyric acid (GABA). The hypothalamic peptide, orexin (i.e.,
hypocretin), likely mediates hypothalamic DA release and is implicated in reward
pathways and the maintenance of wakefulness (Baumann and Bassetti 2005; Narita
et al. 2006). Orexin antagonists are currently used for treatment of narcolepsy, a
sleep/arousal disorder characterized by REM abnormalities and excessive daytime
sleepiness (Deats et al. 2015). Glutamate is one of the primary neurotransmitters
responsible for mediating the synchronization of light, and acts upon NMDA and
AMPA/kainate receptors (Golombek and Rosenstein 2010). NMDA receptors are
found on GABA neurons inside the thalamic reticular nucleus. Ketamine is a
NMDA receptor antagonist currently under investigation as a rapidly acting
antidepressant (Machado-Vieira et al. 2015). Ketamine reduces GABA release and
leads to excessive DA production (Moghaddam et al. 1997). Animal studies suggest
that ketamine may enhance excitatory synaptic function in some brain regions (e.g.,
hippocampus and frontal cortex) while dampening excitatory connectivity in
regions that are overactive in MDD (e.g., affective and cognitive control networks).
Furthermore, ketamine increases slow wave sleep activity during NREM sleep
(Duncan et al. 2013). Of note, NMDA receptor antagonists are the only pharma-
cological treatments for MDD that exert rapid and robust antidepressant effects
within hours or days (Sanacora et al. 2008). Sleep deprivation therapy is the only
treatment for MDD that yields a comparably rapid and robust response.
Greater understanding of the common signaling pathways that mediate the rapid
antidepressant effects of sleep deprivation therapy and ketamine may enhance our
understanding of the sleep architecture-mediated and circadian-mediated DAergic
changes seen in depression. The mesolimbic DA system has been implicated
separately in insomnia, circadian rhythm disruption, and depression. Thus, there is
evidence that alterations in mesolimbic DAergic functioning may underlie the
comorbidity of insomnia and depression. Further investigations of the pathways
involved with DAergic signaling may provide more efficient and efficacious
pharmacological and nonpharmacological treatment strategies for depression and
insomnia.
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kwu245
Sleep in Schizophrenia Patients
and the Effects of Second Generation
Antipsychotic Drugs
Jaime M. Monti, Pablo Torterolo and Seithikurippu R. Pandi

Perumal
Abstract Insomnia is a common feature in schizophrenia, and is characterized by

an increase of sleep onset latency (SOL), and a reduction of total sleep time (TST),
sleep efficiency (SE), and rapid-eye-movement (REM) sleep latency, but REM
sleep percentage remain unchanged. According to polysomnographic studies, the
administration of clozapine, olanzapine and paliperidone to schizophrenia patients
was followed by a significant reduction of SL and an increase of TST and stage S2.
In addition, olanzapine and paliperidone augmented SE, slow wave sleep
(SWS) and REM sleep. In contrast, quetiapine administration further disrupted
sleep as judged by an increase of SOL, wake time after sleep onset (WASO) and
REM sleep latency, and a reduction of SWS and REM sleep. With respect to
risperidone, available information tends to indicate that the compound increases
SWS. To date, no polysomnographic studies have been published on the effects of
ziprasidone, aripiprazole, asenapine, iloperidone and lurasidone on sleep in
schizophrenia patients. Somnolence is a common side-effect in patients receiving
clozapine, olanzapine, asenapine and iloperidone, followed by ziprasidone and
quetiapine. In contrast, insomnia is frequently reported by patients taking arip-
iprazole and lurasidone.

Keywords Schizophrenia Second generation antipsychotics Insomnia disor-

der NREM sleep REM sleep Wakefulness
J.M. Monti (&)

Department of Pharmacology and Therapeutics, School of Medicine
Clinics Hospital, Montevideo, Uruguay
e-mail: jmonti@mednet.org.uy
P. Torterolo
Department of Physiology, School of Medicine, Montevideo, Uruguay
S.R. Pandi Perumal
Somnogen Canada Inc., College Street, Toronto, ON, Canada

DOI 10.1007/978-3-319-46437-4_10
214 J.M. Monti et al.
1 Normal Sleep
Sleep is closely connected to many facets of health and well-being and physical and
mental functioning. In this respect, disturbed sleep not only affects health-related
quality of life, but also causes significant public health concern worldwide. The
initial system for scoring sleep stages, based on polysomnography (PSG), as pro-
posed by Rechtschaffen and Kales (1968) recognized a waking (W) state,
non-rapid-eye-movement (NREM) sleep and rapid-eye-movement (REM)
sleep. Accordingly, during NREM sleep four stages were distinguished. The young
adult spends 20–28 % of a night’s sleep (7–8 h) in REM sleep, 4–5 % in stage 1
sleep (S1-light sleep), 46–50 % in stage 2 (S2—intermediate sleep), 6–8 % in stage
3 (S3), and 10–16 % in stage 4 (S4) NREM sleep. Stages 3 and 4 have been
collectively known as slow wave sleep (SWS) or deep sleep. Total sleep time
(TST), sleep efficiency (SE), and percentage of SWS and REM sleep diminish
through maturity and old age, whereas percentage of S1 and S2 increases with age.
The American Academy of sleep Medicine (AASM) introduced new guidelines to
score all-night polysomnographic recordings (Iber et al. 2007), which differ from
those recommended by the Rechtschaffen and Kales rules in that light sleep (S1 vs.
N1) and deep sleep (S3 + S4 vs. N3) are significantly increased while intermediate
sleep (S2 vs. N2) is reduced (Moser et al. 2009). Sleep stages reported in recent
polysomnographic (PSG) studies that included either untreated or medicated
patients with a diagnosis of primary or comorbid insomnia were mostly based on
the sleep scoring rules and terminology developed by Rechtschaffen and Kales
(1968).
2 Insomnia: Diagnostic Criteria
Insomnia disorder is a complaint of dissatisfaction with sleep quantity or quality,

associated with difficulty falling asleep (sleep latency greater than 20–30 min) or
staying asleep. The latter is characterized by numerous nocturnal awakenings,
problems returning to sleep after awakenings, and early morning awakening with
inability to resume sleep. Usually, time awake after sleep onset amounts to more
than 20–30 min, early morning awakening occurs at least 30 min before the
scheduled time, and TST amounts to less than 6.5 h (American Psychiatric
Association 2013). These sleep difficulties are accompanied by daytime symptoms.
Common daytime complaints include somnolence, fatigue, irritability, difficulty
concentrating and performing everyday tasks. In addition, subjects with a diagnosis
of insomnia are at risk for injury, drowsiness while driving, and illness. As a rule,
the sleep disturbance occurs at least 3 nights per week, and persists for a minimum
of 3 months (American Psychiatric Association 2013). Female gender and
advancing age are associated with an increased incidence of insomnia.
Sleep in Schizophrenia Patients and the Effects … 215
The International Classification of Sleep Disorders (ICSD-2) (2005) considers

severity (mild, moderate and severe) and duration (transient, short-term and
chronic) of insomnia as important guides to its evaluation and treatment. Chronic
insomnia in adult patients has been classified as primary or comorbid. When there is
no other diagnosable condition directly associated with the chronic insomnia, it is
diagnosed as primary insomnia. If the insomnia is precipitated or aggravated by a
psychiatric or neurological disease, a general medical condition, another sleep
disorder, a disturbance of circadian rhythm, or the direct effects of a medication or a
substance of abuse, then the other disorder is termed secondary or comorbid
insomnia (Lichstein et al. 2006).
The new Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
(DSM-5) and the International Classification of sleep Disorders (ICSD-3) (2014)
have been moved away from the causal attributions present in DSM-4 and the
ICSD-2 sleep-wake disorders classification, and consider that sleep disorders and
coexisting neuropsychiatric and medical co-morbidities are interactive and bidi-
rectional. In this respect, these two manuals propose to rename primary insomnia
and comorbid insomnia as an insomnia disorder (Reynolds and O’Hara 2013).
In sleep disorder centers, about 15 % of all insomniacs are diagnosed with
primary insomnia. Comorbid insomnia is the most frequent form of insomnia and is
predominantly associated with depressive and anxiety disorders (45–50 % of cases)
(Sateia 2009).
3 Sleep Disturbance in Schizophrenia
Schizophrenia is a psychotic disorder that typically presents in the early- mid-20s

for men and about five years later for women. It is characterized by the presence of
delusions, hallucinations, disorganized speech, catatonic behavior, and decreased
emotional expression that persist for at least 6 months. Its lifetime prevalence is
0.3–0.7 %. Approximately 5–6 % of schizophrenic patients die by suicide
(American Psychiatric Association 2013).
Subjective sleep dysfunction in patients with a diagnosis of schizophrenia
includes insomnia or excessive sleepiness. Total sleeplessness is frequently
observed during acute exacerbation of the mental disorder. There may also be a
partial or complete inversion of the day-night cycle, such that the patient sleeps
predominantly during the day and stays awake at night (American Academy of
Sleep Medicine 2005). With respect to objective sleep changes the following are
noted: 1. S2 sleep onset latency (SOL), wake time after sleep onset (WASO) and
the number and duration of awakenings are increased; stages S2 and S4, TST and
SE are reduced; REM sleep time and density of eye movements tend to remain
unchanged, whereas REM sleep latency is inconsistently reduced (Monti and Monti
2005; Staner et al. 2008; Winokur and Kamath 2008). Studies involving waking
electroencephalogram (EEG) spectral analysis have shown that patients with
schizophrenia have less delta (0.75–3.75 Hz) and alpha (8.0–12.75 Hz), and more
beta2 (20.0–30.75 Hz) and gamma (35.0–45.0 Hz) spectral power compared to
healthy controls (Kemali et al. 1992; Hoffman et al. 2000; Tekell et al. 2005;
Sekimoto et al. 2007). Lower alpha and higher beta2 spectral amplitude have been
found also during REM sleep in patients with first-episode schizophrenia (Poulin
et al. 2008).
4 Pharmacotherapy of Schizophrenia
Antipsychotic drugs are an essential component of the treatment of schizophrenia.

Presently available drugs for the treatment of schizophrenia are divided into first
generation agents (FGAs) and second generation agents. Second generation
antipsychotic drugs (SGAs) comprise a varied group of compounds that include
(listed according to the year they were brought to market) clozapine (1989),
risperidone (1993), olanzapine (1996), quetiapine (1997), ziprasidone (2001),
aripiprazole (2002), paliperidone (2006), asenapine (2009), iloperidone (2009) and
lurasidone (2010). All these compounds offer advantages over first generation
antipsychotic drugs including a greater improvement in negative symptoms and
cognitive impairment with low propensity for extrapyramidal symptoms and tardive
dyskinesia. Notwithstanding this, hyperglycemia, weight gain and dyslipidemia
have been described during their administration (Leucht et al. 2013). Of note, with
the advent of the SGAs, other psychiatric disorders including major depressive
disorder (MDD) and bipolar depression are treated also with these drugs.
5 Preclinical Pharmacology, Receptor Binding Affinity

and Pharmacokinetics of Second Generation
Antipsychotic Drugs
The preclinical pharmacology profile, binding affinity for a number of receptor

subtypes and pharmacokinetics of SGAs can tentatively predict their effects on
sleep variables in subjects with normal sleep and patients with psychiatric disorders.
5.1 Preclinical Pharmacology of Second Generation

Antipsychotic Drugs
Several animal behavioral models mediated by dopaminergic mechanisms have

been used to predict the efficacy of SGAs in patients with schizophrenia. As a
whole, they detect preferential effects of the SGAs on mesolimbic dopaminergic
neurons as compared to nigrostriatal neurons (Frangou and Murray 1996).
The screening tests comprise: (a) inhibition of escape or conditioned avoidance

response (CAR) to an aversive stimulus following a warning stimulus in rodents;
(b) reduction of spontaneous motor activity induced by amphetamine; (c) reversal
of apomorphine or amphetamine-induced reduction in latent inhibition; (d) reversal
of social isolation induced by amphetamine in the monkey.
(a) Second generation antipsychotic agents including clozapine, risperidone,
olanzapine, quetiapine, ziprasidone, aripiprazole and asenapine impair the
ability of rodents to make a CAR at doses below those inducing catalepsy but
close to those inhibiting exploratory behavior (Frånberg et al. 2008). The high
affinity binding for a1 receptor by some of these compounds has been pro-
posed to contribute to their effect on the conditioned response.
(b) Nearly all SGAs inhibit hyperactivity induced by amphetamine 0.5 mg/kg
without effects on stereotyped behavior and catalepsy (Baldessarini and Tarazi
2001).
(c) Deficits of prepulse inhibition produced by the dopaminergic agonist apo-
morphine have been shown to be reversed by clozapine, risperidone, olan-
zapine and quetiapine. In contrast, aripiprazole prevents prepulse inhibition
related to amphetamine, but not to apomorphine administration (Arnt and
Skarsfeldt 1998).
(d) Deficits in social interaction induced by amphetamine in monkeys are reversed
by the SGAs. In this respect, clozapine and quetiapine have been shown to
induce the most consistent effects on social deficits (Baldessarini and Tarazi
2001).
In conclusion, animal behavioral models show that inhibition of dopaminergic
mechanisms are involved in the impairment of escape response and
amphetamine-induced increase of spontaneous motor activity, reduction in latent
inhibition and reversal of social isolation.
5.2 Receptor Binding Affinity of Second Generation

Antipsychotic Drugs
The dopamine (DA) hypothesis of schizophrenia, formulated in the 1960s on the

basis of indirect evidence, states that the symptoms of schizophrenia depend upon
the overactivity of the dopaminergic system (Carlsson and Lindqvist 1963).
Positron emission tomography (PET) and single-photon emission tomography
(SPECT) studies tend to indicate that the major dopaminergic abnormalities consist
of increased DA synthesis and release, and to a lesser extent, augmented D2/D3
receptor density. In contrast, DA transporter availability is not modified
(Abi-Dargham et al. 2000; Howes et al. 2013). Additional studies have led to the
proposal that the dysregulation of the serotonergic, c-aminobutyric acid (GABA)
ergic and glutamatergic neurotransmitter systems is implicated also in the etiology
of schizophrenia. In this respect, (a) magnetic resonance spectroscopy has detected

excessive serotonergic stimulation in the cerebral cortex of schizophrenia patients.
Moreover, blockade of serotonin (5-HT) 5-HT2A receptors by SGAs decelerates
the course of the disease (Eggers 2013); (b) low GABA levels have been found in
the amygdala, hippocampus and cerebral cortex of schizophrenia patients. The
increase of GABAA receptor expression observed in some of these neuroanatomical
structures would depend on a compensatory up-regulation of GABA receptors
postsynaptically (Lieberman et al. 2008); (c) The proposal that a deficient activity at
glutamate synapses could be implicated in the pathophysiology of schizophrenia is
supported by the finding that N-methyl-D-aspartate (NMDA) receptor antagonists
elicit behavioral effects in humans and monkeys similar to the symptoms described
in schizophrenia patients. Accordingly, healthy human subjects given ketamine
displayed acute effects that resembled positive and negative symptoms and cog-
nitive deficits of schizophrenia (Krystal et al. 1994). Moreover, monkeys admin-
istered phencyclidine showed behavioral impairments and decreased DA utilization
in the prefrontal cortex that were relieved by clozapine (Jentsch et al. 1997).
With one exception, all SGAs approved for clinical use by governmental
agencies are D2 receptor antagonists. The only current exception is aripiprazole,
which is a partial D2 receptor agonist. Additionally, SGAs can block DA D1, D3
and D4 receptors; 5-HT 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7 receptors;
noradrenergic (NE) a1 and a2 receptors; histaminergic (HA) H1 receptors, and
muscarinic cholinergic (ACh) m1 receptors. Second generation antipsychotic agents
can interact also with the DA, 5-HT and NE transporter (Shin et al. 2011).
To date, PSG studies have been published exclusively on the effects of cloza-
pine, risperidone, olanzapine, quetiapine and paliperidone on sleep of schizophrenic
patients. Thus, the description of receptor binding properties and pharmacokinetics
will be restricted to the above mentioned SGAs.
The receptor interactions among these drugs (Table 1) are as follows:
– clozapine affinity: high for 5-HT2A, a1, H1 and m1 receptors; moderate for
5-HT2C, 5-HT6 and 5-HT7 receptors and DAT (DA transporter); low for D1, D2
and a2 receptors and NAT (norepinephrine transporter), and minimal to none for
5-HT1A receptor.
– risperidone affinity: high for D2, 5-HT2A, 5-HT7 and a1 receptors; moderate for
5-HT2C and a2 receptors; low for H1 receptor, and minimal or none for 5-HT1A,
5-HT6 and m1 receptors.
– olanzapine affinity: high for 5-HT2A, H1 and m1 receptors; moderate for D1, D2,
5-HT2C and a1 receptors, DAT and NAT; low for 5-HT6 and a2 receptors, and
minimal or none for 5-HT1A and 5-HT7 receptors.
– quetiapine affinity: high for a1 receptor; moderate for 5-HT2A, H1 and m1
receptors; low for D2 receptor, and minimal or none for D1, 5-HT1A, 5-HT2C,
5-HT6, 5-HT7 and a2 receptors.
– paliperidone affinity: high for 5-HT2A receptor; moderate for D2, a1 and a2
receptors; low for D1, 5-HT1A, 5-HT2C and H1 receptors, and minimal or none
for 5-HT6, 5-HT7 and H1 receptors.
Table 1 Relative receptor affinities of second generation antipsychotic drugs
Receptor D1 D2 5-HT1A 5-HT2A 5-HT2C 5-HT6 5-HT7 a1 a2 H1 m1
Clozapine + + − +++ ++ ++ ++ +++ + +++ +++
Risperidone + +++ − +++ ++ − +++ +++ ++ + −
Olanzapine ++ ++ − +++ ++ + − ++ + +++ +++
Sleep in Schizophrenia Patients and the Effects …
Quetiapine − + − ++ − − − +++ − ++ ++
Paliperidone + ++ + +++ + − − ++ ++ + −
From Horacek et al. (2006), Jarskog et al. (2007), Dolder et al. (2008), Shin et al. (2011)
+++ = high; ++ = moderate; + = low; − = minimal to none
219
5.3 Pharmacokinetics of Second Generation Antipsychotic

Drugs
Most SGAs are highly lipophilic and tend to accumulate in the central nervous
system (CNS) and peripheral structures with a rich blood supply. The absorption,
metabolism and elimination of each of the SGAs in clinical use will be briefly
described (Table 2).
– clozapine’s oral bioavailability is only 60–70 % due to first-pass metabolism,
and the peak plasma concentration (Tmax) amounts to 2–5 h. Clozapine is
metabolized in the liver preferentially by the enzyme CYP1A2. The major
metabolite N-desmethylclozapine (norclozapine) is pharmacologically active.
The mean elimination half-life (t½) of clozapine and its active metabolite
amounts to about 12 h (Baldessarini and Tarazi 2001).
– risperidone is well absorbed, and its absolute bioavailability is 70 %. The
compound is metabolized in the liver by CYP2D6 to an active metabolite,
9-hydroxyrisperidone (paliperidone). Following oral administration of solution
or tablet Tmax of the parent drug occurs at 1 h, while this corresponding to
9-hydroxyrisperidone occurs at about 3 h in extensive metabolizers. The mean
t½ of both drugs amounts to 20 h. Risperidone’s active metabolite is excreted in
urine and feces (Heykants et al. 1994).
– olanzapine is well absorbed, with approximately 40 % of a therapeutic dose
being metabolized before reaching the systemic circulation. The compound
attains peak plasma levels (Tmax) at about 6 h after oral administration, and its
t½ ranges from 21–54 h. It is metabolized by hepatic CYP1A2 and CIP2D6 to
inactive metabolites that are excreted in urine and feces (Callaghan et al. 1999).
– quetiapine is rapidly absorbed after oral administration with median time to
reach Tmax ranging from one to two hours. The relative bioavailability from
orally given tablets compared with a solution is almost complete. The drug is
metabolized predominantly by hepatic CYP3A4 to its active metabolite
Table 2 Pharmacokinetic parameters for second generation antipsychotic drugs

Drug Peak plasma concentration Elimination Metabolism (active
(Tmax-h) half-life (t½-h) metabolites)
Clozapine 2–5 12 N-desmethylclozapine
Risperidone 1 20 9-hydroxyrisperidone
Olanzapine 6 21–54 No
Quetiapine 1–2 7 Norquetiapine
Paliperidone 24 21 No
ERa
From Baldessarini and Tarazi (2001), Heykants et al. (1994), Callaghan et al. (1999), DeVane and
Nemeroff (2001), Vermeir et al. (2008)
a
ER: extended-release
norquetiapine that is excreted in urine and feces. Quetiapine is eliminated with a

t½ of seven hours, while values corresponding to norquetiapine amount to 9–
12 h (DeVane and Nemeroff 2001).
– paliperidone (9-hydroxyrisperidone) is the major and active metabolite of
risperidone. When paliperidone extended-release (ER) is given by oral route its
bioavailability amounts to 28 %, and peak concentrations (Tmax) occur at about
24 h. The t½ of paliperidone is about 21 h in extensive metabolizers. The
compound is metabolized by CYP2D6 and CYP3A4, and inactive metabolites
are excreted via urine and feces (Vermeir et al. 2008).
6 Effects of SGAs on Sleep Variables in Schizophrenia

Patients
In all instances the study authors made use of a sleep laboratory to obtain objective
evidence of the effects of SGAs on sleep induction and continuity measures, and on
sleep architecture. The all-night PSG evaluation of sleep in schizophrenia patients
treated with SGAs was compared with that of drug-naïve patients, drug-free
patients, subjects with normal sleep, baseline, placebo or another antipsychotic
drug.
6:1 Clozapine is effective in treating treatment-resistant schizophrenia, and its use
requires regular white blood cell and absolute neutrophil counts (Meltzer
1997).
Wetter et al. (1996) compared the nocturnal EEG recordings of drug-naïve
schizophrenia patients with those of patients treated with clozapine
(348.0 ± 152.0 mg). Values corresponding to S2 sleep, TST and SE were signif-
icantly greater while SOL was smaller in the clozapine-treated group as compared
to the untreated patients. Values related to REM sleep variables showed no sig-
nificant changes (Table 3).
Hinze-Selch et al. (1997) conducted a two-week PSG study in long-term
drug-free schizophrenia patients. Clozapine administration
(170.0 ± 77.0/275.0 ± 122.0 mg) induced a significant increase of S2 sleep, TST
and SE from baseline to week one and again from week one to week two. In
contrast, WASO, S4 sleep and SWS decreased significantly (Table 3).
In the study by Tandon (1997), the sleep-EEG profile of schizophrenia patients
receiving clozapine was compared to that of drug-free patients. Clozapine induced a
significant decrease of S2 sleep latency whereas TST and REMS latency were
augmented (Table 4).
Lee et al. (2001) determined the effects of clozapine (200.0/350.0 mg) on
schizophrenia patients who were drug- free for periods ranging from 16 to 31 days.
Compared with healthy subjects, S2 sleep, TST and SE were significantly increased
during early and late clozapine therapy (Table 4).
Table 3 Effects of clozapine on sleep variables in schizophrenia patients

Wetter et al. (1996)
Drug naïve Clozapine
Sleep induction
– S2 sleep latency (min) 55.5 ± 54.5 16.1 ± 10.0a
Sleep continuity
– WASO (min) 32.6 ± 29.8 23.3 ± 41.3ns
– Total sleep time (min) 361.1 ± 59.4 432.1 ± 49.9a
– Sleep efficiency (%) 77.6 ± 11.4 91.2 ± 10.6a
Sleep architecture
– S1 sleep (min) 23.6 ± 15.5 17.2 ± 11.2ns
– S2 sleep (min) 197.0 ± 34.7 86.3 ± 35.7a
– S3 sleep (min) 32.1 ± 19.6 37.5 ± 26.0ns
– S4 sleep (min) 22.3 ± 30.4 7.5 ± 9.7ns
– Slow wave sleep (min) Not available
– REMS latency (min) 67.8 ± 40.7 113.7 ± 56.4ns
– REMS (min) 75.9 ± 31.7 75.6 ± 24.9ns
Hinze-Selch et al. (1997)
Baseline Clozapine
Week 1 Week 2
Sleep induction
– S2 sleep latency (min) 33.3 ± 32.3 17.7 ± 14.9ns 10.7 ± 7.7ns
Sleep continuity
– WASO (min) 68.0 ± 43.6 22.8 ± 19.0c 19.0 ± 12.3c
– Total sleep time (min) 406.7 ± 41.9 454.7 ± 22.2 d
464.0 ± 14.4d
– Sleep efficiency (%) 92.1 ± 7.6 97.5 ± 2.8 b
97.4 ± 2.4b
Sleep architecture
– S1 sleep (min) 32.5 ± 10.8 23.1 ± 10.7ns 27.1 ± 17.8ns
– S2 sleep (min) 226.2 ± 43.1 313.7 ± 51.1 d
316.8 ± 37.5d
– S3 sleep (min) 33.1 ± 13.6 26.0 ± 24.4 ns
31.5 ± 37.0ns
– S4 sleep (min) 24.5 ± 20.5 12.7 ± 18.4 c
7.0 ± 9.9c
– Slow wave sleep (min) 57.6 ± 31.6 38.7 ± 41.8 b
38.5 ± 46.4b
– REMS latency (min) 72.2 ± 45.0 96.8 ± 64.7 ns
89.1 ± 32.2ns
– REMS (min) 86.6 ± 27.4 77.3 ± 23.5 ns
79.1 ± 31.7ns
Clozapine significantly different from drug naïve: ap < 0.05; ns non-significant; WASO wake time
after sleep onset
Clozapine significantly different from baseline: bp < 0.05; cp < 0.01; dp < 0.001
It can be proposed that clozapine therapy resulted in a significant improvement

of sleep continuity in schizophrenia patients as judged by the consistent increase of
TST. The increase of TST was related to the occurrence of greater amounts of S2
sleep. The high affinity of clozapine for H1, a1 and m1 receptors could be the basis
of an increase of TST and its marked sedative properties. Additionally, clozapine
Table 4 Effects of clozapine on sleep variables in schizophrenia patients

Tandon (1997)
Drug free period Clozapine
Sleep induction
– S2 sleep latency (min) 72 ± 54 40 ± 41a
Sleep continuity
– WASO (min) Not available
– Total sleep time (min) 310 ± 80 354 ± 74a
– Sleep efficiency (%) Not available
Sleep architecture
– S1 sleep (min) Not available
– Slow wave sleep (%) 10 ± 10 14 ± 15ns
– REMS latency (min) 52 ± 35 72 ± 46a
– REMS (min) 74 ± 23 77 ± 24ns
Lee et al. (2001)
Healthy subjects Clozapine
Day 4 Day 46
Sleep induction
Sleep continuity
– Total sleep time (min) 282.0 ± 56.0 402.6 ± 29.2b 350.8 ± 77.4b
– Sleep efficiency 63.4 ± 14.2 88.8 ± 4.3b 81.2 ± 15.1b
Sleep architecture
– S1 sleep (min) 13.6 ± 13.8 8.1 ± 2.9ns 9.9 ± 4.4ns
– S2 sleep (min) 141.2 ± 49.7 220.7 ± 21.0 c
183.5 ± 54.5c
– Slow wave sleep (min) 67.0 ± 43.6 67.2 ± 23.6ns 86.9 ± 44.7ns
– REM sleep latency (min) 115.3 ± 49.8 109.4 ± 32.8 ns
104.9 ± 55.3ns
– REMS (min) 61.5 ± 42.5 95.9 ± 20.4 ns
70.1 ± 24.7ns
Clozapine significantly different from drug-free: ap < 0.05; ns non-significant
Clozapine significantly different from baseline: bp < 0.05; cp < 0.01
displays high affinity for 5-HT2A receptor. Following its blockade, however SWS
remained unchanged or even decreased.
6:2 Risperidone is used for the treatment of schizophrenia including relapse pre-
vention (Leucht et al. 2013). In addition, the antipsychotic is effective in the
treatment of manic symptoms in acute manic or mixed exacerbations of
bipolar disorder (Muralidharan et al. 2013).
Tandon (1997) characterized the sleep-EEG profiles of schizophrenia patients

who were on a stable dose of risperidone for a minimum of two weeks. The only
significant difference between risperidone-treated and drug-free patients was a
decrease of sleep latency. Sleep continuity and sleep architecture measures were not
significantly modified during drug treatment (Table 5).
Yamashita et al. (2002) compared also the effects of risperidone (6.4 ± 3.7 mg)
on sleep measures in patients with schizophrenia with those of patients receiving
haloperidol (7.5 ± 4.0 mg). The duration of SWS was significantly longer in the
risperidone-treated than haloperidol group. There were no significant differences
between the two groups with respect to sleep induction or sleep continuity
(Table 5).
Of interest, Gao et al. (2013) determined the incidence of somnolence associated
with risperidone relative to placebo in patients with schizophrenia. It was reported
that the compound had no increased risk for somnolence relative to placebo.
Risperidone exerts high antagonism at the D2, 5-HT2A and a1 receptors.
Notwithstanding this, the antipsy-chotic failed to increase TST in the schizophrenia
patients. However, in order to draw definite conclusions, further studies are
warranted.
6:3 Olanzapine is indicated for the acute and maintenance treatment of
schizophrenia and related disorders, as well as acute treatment of mixed epi-
sodes of bipolar disorder (Citrome 2012).
Salin-Pascual et al. (1999) analyzed the effects of olanzapine 10 mg given one
hour before bedtime, on sleep variables during two nights in drug-free phrenia
patients. Compared with baseline measures sleep continuity had an overall
improvement with olanzapine such that WASO was significantly decreased and
TST augmented. Concerning sleep architecture, the main changes comprised a
significant reduction of S1 sleep and an increase of S2 sleep and SWS. There were
no alterations in REM sleep time and latency (Table 6). During a second experi-
ment, Salin-Pascual et al. (2004) compared sleep variables of schizophrenia patients
treated with olanzapine 10 mg during two nights with a group of normal subjects.
Compared to the normal controls, olanzapine significantly reduced SL and
enhanced TST, SWS and REM sleep. In addition, the authors could establish that
the increase of delta sleep after olanzapine administration was predictive of a good
clinical response to the compound.
Müller et al. (2004) investigated the effects of olanzapine (15–20 mg) on sleep
EEG in drug-free schizophrenic patients. Compared with the drug-free period,
treatment with olanzapine for four weeks shortened SL and increasedTST, SE,
SWS and REM sleep. SWS increase was related to greater amounts of S3 and S4
sleep (Table 6). The EEG frequency bands showed no statistically significant
effects on the power of the EEG.
Kluge et al. (2014) assessed the effects of olanzapine 15 mg before and after
two, four and six weeks of treatment on sleep variables in schizophrenic patients.
Compared with baseline the antipsychotic significantly increased TST, SE and
Table 5 Effects of risperidone on sleep variables in schizophrenia patients

Tandon (1997)
Drug-free period Risperidone
Sleep induction
– S2 sleep latency (min) 72 ± 54 40 ± 45a
Sleep continuity
– Total sleep time (min) 310 ± 80 360 ± 85ns
Sleep architecture
– Slow wave sleep (%) 10 ± 10 13 ± 10ns
– REMS latency (min) 52 ± 35 71 ± 35ns
– REMS (min) 74 ± 23 80 ± 20ns
Yamashita et al. (2002)
Haloperidol alone Risperidone alone
Sleep induction
– S2 sleep latency (min) 55.3 ± 39.0 30.2 ± 22.4ns
Sleep continuity
– WASO (min) 46.6 ± 17.9 38.9 ± 25.5ns
– Total sleep time (min) 451.3 ± 59.5 444.3 ± 76.1ns
– Sleep efficiency (%) 90.7 ± 3.3 91.3 ± 7.1ns
Sleep architecture
– S1 sleep (min) 40.8 ± 23.1 64.1 ± 21.0ns
– S2 sleep (min) 235.3 ± 44.7 177.6 ± 56.7ns
– Slow wave sleep (min) 102.3 ± 14.1 132.3 ± 25.2b
– REMS (min) 73.7 ± 12.9 70.3 ± 21.9ns
a
Clozapine significantly different from baseline: p < 0.05; ns non-significant
Risperidone significantly different compared with haloperidol: bp < 0.05
reduced SL during the whole period of drug administration. Concerning sleep

architecture, olanzapine augmented S2 sleep, SWS and REM sleep. The greater
amounts of SWS were dependent upon the increase of both, S3 and S4 sleep
(Table 7).
Gao et al. (2013) assessed the median time to onset, duration and rate of som-
nolence associated with olanzapine administration to schizophrenia patients.
Olanzapine had the highest rate of somnolence relative to placebo and other drugs.
Table 6 Effects of olanzapine on sleep variables in schizophrenia patients

Salin-Pascual et al. (1999)
Baseline Olanzapine
Night 1 Night 2
Sleep induction
Sleep continuity
– WASO (min) 138.8 ± 86.9 70.2 ± 56.3c 59.8 ± 55.5c
– Total sleep time (min) 346.9 ± 93.3 416.1 ± 57.1b 421.9 ± 4.9b
Sleep architecture
– S1 sleep (min) 41.6 ± 35.6 21.7 ± 18.0c 32.7 ± 30.8c
– S2 sleep (min) 194.8 ± 80.5 247.3 ± 57.6a 205.4 ± 71.4ns
– Slow wave sleep (%) 34.7 ± 41.7 76.9 ± 55.7b 98.4 ± 66.7b
– REMS latency (min) 147.5 ± 124.1 184.8 ± 102.1ns 131.1 ± 56.6ns
– REMS (min) 69.7 ± 42.6 63.8 ± 26.6ns 86.0 ± 44.4ns
Müller et al. (2004)
Drug-free period Olanzapine
Sleep induction
– S2 sleep latency (min) 43.3 ± 11.5 25.6 ± 19.1c
Sleep continuity
– Total sleep time (min) 415.0 ± 47.8 453.9 ± 19.9e
– Sleep efficiency (%) 0.8 ± 0.1 0.9 ± 0.1f
Sleep architecture
– S1 sleep (min) 41.6 ± 25.7 34.5 ± 20.2ns
– S2 sleep (min) 190.3 ± 43.5 200.7 ± 48.4ns
– S3 sleep (min) 17.2 ± 8.4 29.4 ± 6.3g
– S4 sleep (min) 57.5 ± 39.3 77.9 ± 45.0g
– Slow wave sleep (%) 74.7 ± 39.4 107.3 ± 45.7g
– REMS (min) 63.0 ± 30.5 83.5 ± 22.3g
Olanzapine significantly different from baseline: ap < 0.05; bp < 0.002; cp < 0.001; ns
non-significant
Olanzapine significantly different from baseline: dp < 0.04; ep < 0.02; fp < 0.01; gp < 0.005
Olanzapine acts as an antagonist and exhibits high affinity for 5-HT2A, H1 and
m1 receptors, and moderate affinity for D2 and a1 receptors. As shown before,
olanzapine effects on sleep architecture (see above) in schizophrenia patients, may
be due to its inhibitory effect on receptor subtypes involved in the occurrence of W
(Monti 2013).
Table 7 Effects of olanzapine on sleep variables in schizophrenia patients

Kluge et al. (2014)
Baseline Olanzapine
Week 2 Week 4 Week 6
Sleep induction
– S2 sleep latency 42.2 ± 30.2 20.7 ± 14.6 18.7 ± 22.3 19.4 ± 20.4
(min)a
Sleep continuity
– WASO Not available
– Total sleep time 350.9 ± 75.4 444.2 ± 14.8 451.3 ± 23.5 459.6 ± 24.8
(min)a
– Sleep efficiency (%)a 83.0 ± 14.0 95.0 ± 3.0 97.0 ± 10.0 97.0 ± 10.0
Sleep architecture
– S1 sleep (min)ns 35.2 ± 20.9 38.1 ± 19.1 28.5 ± 11.2 31.5 ± 19.1
– S2 sleep (min)ab 183.4 ± 60.7 201.5 ± 52.5 200.3 ± 56.1 200.6 ± 40.7
– S3 sleep (min)b 21.9 ± 15.5 46.3 ± 28.4 45.3 ± 28.2 47.0 ± 22.7
– S4 sleep (min)b 32.3 ± 30.5 42.4 ± 30.4 56.5 ± 38.4 50.1 ± 34.6
– Slow wave sleep 54.2 ± 39.7 86.1 ± 54.0 101.7 ± 58.7 95.8 ± 47.6
(min)b
– REMS latency 116.4 ± 57.6 79.8 ± 37.8 87.9 ± 57.5 88.0 ± 55.9
(min)ns
– REMS (min)ab 77.7 ± 24.2 115.9 ± 26.0 118.2 ± 26.1 115.2 ± 25.5
Olanzapine different from baseline: asignificant time effect; bsignificant time-by-treatment effect
6:4 Quetiapine has been approved for the treatment of schizophrenia and bipolar
disorder, and combined with an antidepressant to treat major depressive dis-
order (Wine et al. 2009).
Keshavan et al. (2007) compared sleep variables of quetiapine-treated
schizophrenia patients with drug-naïve patients. The antipsychotic
(313 ± 229 mg) significantly prolonged SL, WASO, REM sleep latency and S2,
and decreased SWS and REM sleep. Total sleep time was not modified. (Table 8).
Loebel et al. (2014) determined the effect of quetiapine XR 600 mg given during
a six-week period on daytime sleepiness in patients with schizophrenia. Compared
to patients receiving a placebo, treatment with quetiapine XR was associated with a
significant increase in daytime sleepiness.
Quetiapine shows high affinity for a1 receptor and moderate affinity for 5-HT2A,
H1 and m1 receptors. The quetiapine-related increase of daytime sleepiness
observed in patients with schizophrenia could be related to its affinity to antagonize
a1, H1 and m1 receptors. However, regardless of its 5-HT2A antagonism, quetiapine
significantly decreased SWS in the schizophrenia patients. Clinical trials and
observations in case studies (Wine et al. 2009), tend to support quetiapine’s
improvement of TST, SE, and subjective sleep scores. Additional PSG studies are
Table 8 Effects of quetiapine on sleep variables in schizophrenia patients

Keshavan et al. (2007)
Drug naive compared with quetiapine
Sleep induction
– S2 sleep latency (min) Increasea
Sleep continuity
– WASO (min) Increasea
– Total sleep time (min) Non-significant
Sleep architecture
– S2 sleep (min) Increasea
– Slow wave sleep (min) Decreasea
– REMS latency (min) Increasea
– REM sleep (min) Decreasea
a
Quetiapine significantly different from drug-naive patients (p < 0.05)
needed to consolidate the effects of the antipsychotic on sleep variables in patients

with schizophrenia and concomitant insomnia.
6:5 Paliperidone is used in schizophrenia, schizoaffective and manic disorders,
and at lower doses as maintenance treatment for bipolar disorder (Janicak and
Winans 2007).
Luthringer et al. (2007) performed a double-blind, placebo-controlled study to
evaluate the effects of paliperidone extended release (ER) 9 mg/day on sleep
variables in patients with schizophrenia. The antipsychotic significantly decreased
SL and augmented TST and SE compared with placebo during nights 14 and 15 of
the drug administration. In addition, paliperidone ER increased stage 2, and REM
sleep, but reduced stage S1 (Table 9). Thus, paliperidone ER improved sleep
induction and several aspects of sleep continuity and architecture. Next-day som-
nolence or insomnia was detected in only 1 out of the 21 patients included in the
study.
Paliperidone shows high affinity for 5-HT2A receptor and moderate affinity for
D2 and a1 receptors. Notwithstanding this, in the study by Üçok et al. (2015)
paliperidone ER 5.9 ± 2.0 mg/day administration during 189 ± 130 days to
patients with recent onset schizophrenia, insomnia was the most common adverse
event, noted in 17.9 % of patients. Further studies, however, are needed before a
definite conclusion can be made regarding benefits of paliperidone ER in
schizophrenia patients associated with an insomnia disorder.
Table 9 Effects of Luthringer et al. (2007)

paliperidone on sleep
Placebo Paliperidone
variables in schizophrenic
patients Sleep induction
– S2 sleep latency (min) 55.1 ± 45.4 35.9 ± 20.6a
Sleep continuity
– WASO (min) 58.3 ± 43.3 58.4 ± 60.2ns
– Total sleep time (min) 356.6 ± 87.7 370.4 ± 74.3a
– Sleep efficiency (%) 74.3 ± 18.1 77.5 ± 15.6a
Sleep architecture
– S1 sleep (min) 24.0 ± 12.0 18.8 ± 17.1a
– S2 sleep (min) 213.1 ± 58.2 219.3 ± 52.5a
– S3 sleep (min) 9.0 ± 7.2 13.1 ± 11.2ns
– S4 sleep (min) 34.3 ± 31.6 39.0 ± 28.2ns
– Slow wave sleep (min) 43.3 ± 36.8 52.2 ± 29.5ns
– REMS (min) 76.1 ± 31.5 80.1 ± 24.6a
Olanzapine significantly different from baseline: ap < 0.05; ns:
non-significant
7 Conclusions
Sleep disturbances of either never-medicated or previously treated schizophrenia

patients are characterized predominantly by a sleep onset and maintenance
insomnia.
The effects of clozapine, risperidone, olanzapine, quetiapine and paliperidone on
been characterized in the sleep laboratory. Studies of sleep in schizophrenia patients
treated with SGAs, however, have failed to generate consistent finding.
Methodological shortcomings including fewer number of patients, and other con-
founding variables such as variation in dosing between studies, age and gender, or
phase of illness may have contributed to such inconsistencies. Despite these
shortcomings, available evidence points to the fact that administration of clozapine,
olanzapine and paliperidone to schizophrenia patients causes a significant reduction
of SL and an increase of TST and stage S2. In addition, olanzapine and paliperidone
enhanced SE, SWS and REM sleep. Administration of quetiapine to schizophrenia
patients further disrupted sleep as judged by an increase of SL, WASO and REM
sleep latency and reduction of SWS and REM sleep. The limited available infor-
mation indicates that risperidone increases SWS in schizophrenia patients.
Improvement of sleep in schizophrenia patients given SGAs is related to the
blockade of HA H1, noradrenergic a1, and cholinergic m1 receptors (Monti 2011a;
Berridge et al. 2012). However, the blockade of DA D2 receptors could partly
contribute to the improvement of sleep (Monti and Jantos 2008).
The increase of SWS after administration of some SGAs could be mediated
through the blockade of 5-HT 5HT2A receptor, as similar increases of SWS have
been observed with selective 5-HT2A receptor antagonists and inverse agonists in
sleep laboratory studies in subjects with normal sleep and patients with an insomnia
disorder (Monti 2011b).
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Sleep in Narcolepsy and the Effects
of Modafinil
Michel Billiard
Abstract Narcolepsy is a rare disease characterized by excessive daytime sleepines

(EDS) and cataplexy (narcolepsy type 1) or EDS without cataplexy (narcolepsy
type 2), plus or minus hypnagogic hallucinations, sleep paralysis and disturbed
nocturnal sleep. Narcolepsy type 1 is caused by a selective loss of hypocretin pro-
ducing cells in the posterior hypothalamus. The pathogenesis is unknown but thought
to be related to an autoimmune process, based on the observation of a tight associ-
ation with the HLA-DQB1*0602 allele and on the recent strong indication of an
antigen presentation to T cells as central factor. In comparison the biological back-
ground of narcolepsy type 2 is less clear and likely heterogeneous. Current treatments
for EDS are symptomatic, including behavioral and pharmacological approaches.
The latter are based on wake-promoting therapeutics that increase dopamine release,
modafinil and armodafinil, stimulants and sodium oxybate a drug known to activate
the Gamma-aminobutyric acid receptor type B (GABA-B receptor)

Keywords Narcolepsy type 1 Narcolepsy type 2 Hypocretin Modafinil

Stimulants Sodium oxybate Novel therapies
1 Introduction
Narcolepsy is a relatively rare disease characterized by excessive daytime sleepi-

ness (EDS) and cataplexy (narcolepsy type 1) or EDS without cataplexy (nar-
colepsy type 2), with or without hypnagogic hallucinations, sleep paralysis and
disturbed nocturnal sleep (American Academy of Sleep Medicine 2014).
Narcolepsy type 1 is caused by a selective loss of hypocretin producing cells in the
hypothalamus, presumably of immunologic origin, in genetically predisposed individ-
uals (Nishino et al. 2001; Thannickal et al. 2000; Peyron et al. 2000; Singh et al. 2013).
M. Billiard (&)
Department of Neurology, Gui de Chauliac Hospital,
80, Avenue Augustin Fliche, 34295, cedex 5 Montpellier, France
e-mail: mbilliard@orange.fr

DOI 10.1007/978-3-319-46437-4_11
236 M. Billiard
The biological background of type 2 narcolepsy is less clear. Treatments of excessive

daytime sleepiness used to rely on stimulants until the arrival on the market of modafinil
in the late 1990s. In this chapter, the sleep symptoms of narcolepsy and their patho-
physiology will first be reviewed, and then the clinical characteristics, mechanisms of
action of modafinil, and the place of modafinil in the treatment of narcolepsy with regard
to stimulants and other awakening drugs will be addressed.
2 Epidemiology
The estimated prevalence of narcolepsy type I is 25–50 per 100.000 and its esti-
mated incidence of 0.74 per 100.000 person years (Silber et al. 2002; Longstreth
et al. 2007). Narcolepsy type 1 may be more frequent in Japan (Honda 1979) and
less frequent in Israel (Lavie and Peled 1987), but the design of these studies was
somewhat questionable. The prevalence of narcolepsy type 2 is uncertain, one of
the reasons being that in the Wisconsin Sleep Cohort Study, 5.9 % of males and
1.1 % of females, all without cataplexy, had a mean sleep latency of 8 min or less
and two or more sleep onset REM periods (SOREMPs) on the multiple sleep
latency test (MSLT) (Mignot et al. 2006). The age of onset varies from childhood to
the 50s, with the main peak around the age of 15 and a second peak around the age
of 36 (Dauvilliers et al. 2001). Most studies have found a slight male predominance.
The condition remains often undiagnosed during many years.
3 Clinical Features
EDS is present in all patients and is usually the first symptom to appear and often
the most disabling one. EDS may manifest itself in different ways. Narcoleptic
patients experience a more or less permanent sleepiness facilitated by monotonous
sedentary situations such as reading, attending a meeting, being passenger in a car,
watching TV. This feeling is released by short naps which typically restore normal
wakefulness for a period ranging from one to several hours, depending on the
severity of the condition. This fact is of considerable diagnostic value. Sleepiness
may also manifest itself as irresistible waves, best described as sleep attacks. These
sleep attacks occur in unexpected circumstances such as in the middle of a con-
versation or a meal, while walking or riding a bicycle, or even while swimming.
They tend to be of short duration, from 15 to 30 min. Finally, EDS may lead to the
patient continuing his or her activity in a semi-conscious manner, hence the patient
writing incomprehensible phrases or speaking incoherently with somebody, a
phenomenon referred to as “automatic behavior.” EDS is sometimes accompanied
by other symptoms such as ptosis, blurred vision or diplopia. It typically develops
over weeks to months but may also start more acutely within days. It is accom-
panied by pronounced difficulty to concentrate and sustain attention leading to
Sleep in Narcolepsy and the Effects of Modafinil 237
impaired performance. It carries an increased risk of traffic or machinery accident. It

impairs the quality of life. In children, the daytime sleepiness will typically present
with the reappearance of daytime naps.
Cataplexy is only present in narcolepsy type 1. It is characterized by a sudden
bilateral loss of muscle tone with preserved consciousness in reaction to emotional
factors which are usually positive such as a fit of laughter, receiving a compliment,
humour expressed by the patient himself, surprise. It lasts from a split second to one
or two minutes. It is pathognomonic of the illness. All the striated muscles can be
affected, with the exception of extrinsic eye muscles and muscles involved in
respiration, leading to the progressive slackening of the whole body, or certain
muscles only like the jaw muscles, responsible for a difficulty in articulating words
or the thigh muscles causing a brief unlocking of the knees. The frequency of
cataplexy is extremely variable from several per day in some patients to only a few
per year in other patients.
The other clinical features are deemed accessory to the extent that they are not
indispensable for the diagnosis of narcolepsy type 1 or 2. Hypnagogic hallucina-
tions are vivid, dreamlike experiences that occur during the transition from
wakefulness to sleep, while hypnopompic hallucinations occur during the transition
from sleep to wakefulness. They may be visual, auditory or tactile. Sleep paralysis
is the inability to move the limbs, head or breathe normally. It is often accompanied
by hypnagogic hallucinations. It is frightening and may last up to 10 min. The
phenomenon is interrupted if the subject is touched. Nocturnal sleep is often dis-
turbed by repeated awakenings, vivid and delusional dreams. Parasomnias are
frequent, including sleep talking and REM sleep behavior disorder, which can be
clinically obvious or only revealed by video-polysomnography (Nightingale et al.
2005). No clear correlation has been established between disturbed nocturnal sleep
and the severity of EDS (Broughton et al. 1994).
Narcolepsy is often associated with other sleep disorders, including periodic
limb movements in approximately 50 % of cases and obstructive sleep apneas.
Among other symptoms are obesity, found in up to 30 % of patients (Kok et al.
2003), depressive mood in 30 % of patients (Fortuyn et al. 2010) and mild to
moderate olfactory dysfunction in 25 % of patients (Bayard et al. 2010).
4 Diagnosis
Narcolepsy type 1 is diagnosed according to the criteria of the International

Classification of Sleep Disorders (ICSD-3), including daily episodes of irrepressible
need to sleep and the presence of one or both polysomnographic features and
biologic features (Table 1) (American Academy of Sleep Medicine 2014).
Narcolepsy type 2 is also diagnosed according to the criteria of the ICSD-3,
including daily episodes of irrepressible need to sleep, absence of cataplexy,
absence of other causes of hypersomnolence, polysomnographic and biologic
features (Table 2) (American Academy of Sleep Medicine 2014).
238 M. Billiard
Table 1 Narcolepsy type 1

ICSD-3 diagnostic criteria
Criteria A and B must be met
A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep
occurring for at least 3 monthsa
B. The presence of one or both of the following:
1. Cataplexy (as defined under Essential Features) and a mean sleep latency of 8 minutes or
less and at least 2 sleep onset REM periods (SOREMPs) on a multiple sleep latency test (MSLT)
performed according to standard techniques. A SOREMP (within 15 min of sleep onset) on the
preceding nocturnal polysomnogram may replace one of the SOREMPs on the MSLTb
2. Cerebrospinal fluid (CSF) hypocretin-1 concentration measured by immunoreactivity, is
either 110 pg/ml or less, or less than 1/3 of mean values obtained in normal subjects using the
same standardized assay
Notes
a
In young children, narcolepsy may sometimes present as excessively long night sleep or as
resumption of previous discontinued daytime napping
b
If narcolepsy type 1 is strongly suspected, clinically but the MSLT criteria of B1 are not met, a
possible strategy is to repeat the MSLT
Table 2 Narcolepsy type 2

ICSD-3 diagnostic criteria
Criteria A-E must be met
A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring
for at least 3 months
B. A mean sleep latency of 8 min or less and at least 2 sleep-onset REM periods (SOREMPs) are found
on an MSLT performed according to standard techniques. A SOREMP (within 15 min of sleep
onset) on the preceding nocturnal polysomnography may replace one of the SOREMPs on the MSLT
C. Cataplexy is absenta
D. Either cerebrospinal fluid (CSF) hypocretin-1 concentration has not been measured or CSF
hypocretin-1 concentration measured by immunoreactivity is either greater than 110 pg/ml, or
greater than 1/3 of mean values obtained in normal subjects with the same standardized assayb
E. The hypersomnolence and/or MSLT findings are not better explained by other causes such as
insufficient sleep, obstructive sleep apnea, delayed sleep phase disorder, or the effect of
medication or substances or their withdrawal
Notes
a
If cataplexy develops later, then the disorder should be reclassified as narcolepsy type 1
b
If the CSF hypocretin-1 concentration is tested at a later stage and found to be either 110 pg/mL or less,
or less than a third of mean values obtained in normal subjects with the same assay, then the disorder
should be reclassified as narcolepsy type 1
5 Course
The general course of narcolepsy is hard to systematize. The pattern tends to be for
EDS and irresistible sleep attacks to occur first and to persist throughout life, even if
improvements are commonly observed after retirement, partly due to a better
schedule of sleep and activity. Cataplexy, hypnagogic hallucinations and sleep
paralysis may disappear spontaneously after a variable number of years, while
disturbed nocturnal sleep does not tend to vanish.
Narcolepsy is more or less debilitating depending on its degree of severity. Some

patients cope with their sleepiness fairly well, using treatment or arranging to take
naps during the day, or a combination of the two, while others are severely
handicapped in relation to impaired driving, machine accidents, deficit in work
performance leading to unemployment and working disability (Daniels et al. 2001).
6 Differential Diagnosis
The presence of cataplexy is pathognomonic of narcolepsy type 1. In the absence of

cataplexy the main differentiated diagnoses include sleep deprivation, hypersomnia
associated with a psychiatric disorder, sleep apnea syndrome, periodic limb
movement disorder, idiopathic hypersomnia, drug intoxication/withdrawal.
7 Pathophysiology
7.1 The Hypocretin System
Narcolepsy type I is linked to the loss of hypocretin neurons. This was first
demonstrated in two animal models (Lin et al. 1999; Chemelli et al. 1999) one year
after, the discovery of a novel hypothalamic peptide neurotransmitter by two inde-
pendent research groups in 1998 (De Lecea et al. 1998; Sakurai et al. 1998). This
neurotransmitter, referred to as hypocretin (De Lecea et al. 1998) or orexin (Sakurai
et al. 1998), is produced by neurons located in the postero-lateral hypothalamus and
projecting to the olfactory bulb, cerebral cortex, thalamus, hypothalamus and
brainstem. All of these structures are important for sleep regulation. Several studies
have shown that the hypocretin system is a major excitatory system that affects the
activity of monoaminergic and cholinergic systems with major effects on wakeful-
ness (Willie et al. 2001; Sakurai 2002). The hypocretin (orexin) system includes two
peptides, hypocretin 1 (orexin A) and hypocretin 2 (orexin B), cleaved from a
common precursor, preprohypocretin. The actions of hypocretins are mediated via
two G-protein-coupled receptors named hypocretin receptor1 (Hcrtr 1) and
hypocretin receptor 2 (Hcrtr 2) also known as orexin-1 (OX1R) and orexin-2 (OX2R)
receptors, respectively. Hcrtr1 is selective for hypocretin-1, whereas Hcrtr 2 is
nonselective for both hypocretin-1 and hypocretin-2.
One year after the discovery of hypocretin, researchers in Stanford identified an
autosomal recessive mutation of Hcrtr 2 (OX2R) in two canine models of nar-
colepsy, Labradors and Dobermans (Lin et al. 1999). At the same time in Dallas,
researchers showed that pre-prohypocretin gene knockout mice were remarkable for
a narcolepsy phenotype with periods of immobility suggestive of cataplexy and
sleep fragmentation (Chemelli et al. 1999).
However, screening of patients with narcolepsy type 1 failed to identify an
hypocretin-related gene mutation, except in the case of a large kindred with familial
narcolepsy reported in Spain, in which a nonsense mutation in the second exon of
myelin oligodendrocyte glycoprotein (MOG) was identified (Hor et al. 2011). On
240 M. Billiard
the other hand, type 1 narcoleptic patients exhibit low or absent CSF hypocretin-1
levels (Nishino et al. 2001) and the analysis of post mortem brain tissue by in situ
hybridization of the perifornical region and radioimmunological peptide assays
revealed almost complete hypocretin peptide loss in the hypothalamus of these
patients (Thannickal et al. 2000; Peyron et al. 2000). Today, it is thought that
symptoms of narcolepsy start to appear when half of hypocretin neurons have
disappeared and that the severity of the condition could depend on the number of
cells lost. In favour of this statement is the documentation of a loss of 90 % of
hypocretin neurons in patients with narcolepsy type 1 versus only 33 % of patients
with narcolepsy type 2 (Thannickal et al. 2009). The absence of other proteins,
dynorphin and neural activity-regulated pentraxin (NARP) co-expressed in a
majority of hypocretin neurons in narcolepsy type-1, suggests a mechanism of
hypocretin cell death as the cause of hypocretine deficiency (Crocker et al. 2005).
7.2 Genetic Aspects
A tight association with the specific human leucocyte antigen class II HLA-DR2 (Juji
et al. 1984), later sublocalized to DQB1*0602 (Mignot et al. 1997), has been
demonstrated. About 98 % of type 1 narcolepsy patients carry this haplotype, com-
pared with only 20–25 % of the general population. Patients homozygous for HLA
DQB1*0602 exhibit a much higher relative risk of acquiring narcolepsy when
compared to heterozygous patients (Tafti et al. 2014), while risk in DQB1*0602
heterozygotes is modulated by the other DQB1 alleles, increased in DQB1*0602/
DQB1*0301 heterozygotes, and decreased in DQB1*0602/DQB1*0601 and
DQB1*0602/DQB1*0501 heterozygotes (Mignot et al. 2001).
Other genetic predisposing factors have been identified, notably genes involved
in the activation of the immune response, even if these associations remain limited
in comparison with HLA-DQB1*0602. Genome-wide association (GNA) studies
performed in various populations including a large number of patients with nar-
colepsy type 1, have shown various associations: a single nucleotide polymorphism
(SNP) rs 1154155 located on the locus coding for the receptor alpha of T cells
(TCRa) situated on chromosome 14 (Hallmayer 2009), a SNP rs 34593439 located
on the locus “cathepsine” (CTSH) on chromosome 15 and a SNP rs 7553711
located in the locus Tumor necrosis factor super family number 4 (TNFSF4) on
chromosome 1 (Faraco et al. 2013). In addition a technique of sequencing of exons
has identified the role of the gene DNMTI (DNA [cytosine-5]—methyltransferase
1), an ADN methylase involved in the process of differentiation of lymphocytes T
CD4* into T regulatory cells, in a rare autosomal dominant cerebellar ataxia
associated with deafness and narcolepsy (ADCA-DN) (Winkelmann et al. 2012).
7.3 Familial Patterns and Environmental Factors
1–2 % of first degree relatives are affected with narcolepsy type1 while a larger
portion of relatives may have isolated excessive daytime sleepiness (Mignot 1998).
Of note, HLA DQB1*0602 positivity is significantly lower in familial cases (70 %)

than in random narcolepsy cases (87 %) (Mignot 2010).
Narcolepsy is not a purely genetic condition. Concordance for narcolepsy was
found in only 25–31 % of monozygotic twins (Mignot 1998), illustrating the
contribution of environmental factors.
Narcolepsy is associated with infections of the upper airway such as streptococcus
pyogenes (Aran et al. 2009) or more probably type A influenza virus (Han et al. 2011).
A recent retrospective analysis of narcolepsy onset in 629 Chinese narcoleptic patients
(86 % children), diagnosed 1998–2010, showed a 3-fold increase in narcolepsy onset
following the 2009 H1N1 influenza pandemic (Han et al. 2011). Notably, the increase
was unlikely to be explained by increased vaccination, as only 8 of 148 (5.6 %)
patients recalled receiving an H1N1 vaccination. However, this association has not
been found in a later French study (Dauvilliers et al. 2013).
Narcolepsy type I incidence increased in Europe following the use of Pandemix,
a 2009 H1N1 AS03-adjuvanted vaccine manufactured by GlaxoSmithKline
(Partinen et al. 2014) favoring an infectious or toxic agent making hypocretin
neurons more vulnerable in genetically predisposed patients.
In conclusion, the generally young age of onset, the association with the major
histocompatibility complex and other genes involved in the immune response, and
the apparent triggering of disease by infection or vaccination, all suggest an
autoimmune basis for hypocretin-deficient narcolepsy, but this has yet to be con-
clusively demonstrated (Mahlios et al. 2013). It is unlikely that the immune response
is directed against hypocretin or preprohypocretin itself, since there is no evidence
for the presence of specific autoantibodies against neuropeptide (Tanaka et al. 2006;
Black et al. 2005a, b). However, an important finding in this context has been the
identification of tribbles homologue 2 (trib 2), colocalized in hypocretin-producing
cells, as a possible autoantigen (Cvetkovic et al. 2010). Autoantibodies against trib 2
have been found in a higher percentage and higher concentration in patients than in
control subjects. Although this is a promising finding, it will be particularly important
to establish a causal pathogenic role of the antigen and antibodies.
In comparison with the pathophysiology of narcolepsy type 1, the pathophysi-
ology of narcolepsy type 2 is not clear. The percent of narcolepsy type 2 patients
with hypocretin deficiency is unknown and the clinical and polysomnographic
phenotype of narcolepsy type 2 patients, with and without hypocretin deficiency
cannot be distinguished. Similarly, the proportion of narcolepsy type 2 patients
positive for HLA DQB1*0602 varies in different series. Thus, narcolepsy type 2 is
most likely an heterogeneous condition.
8 Treatment of Excessive Sleepiness
8.1 Behavioral
A combination of going to bed at the same hour each night and rising at the same
time each morning is recommended. However, the most efficient measure is to take
242 M. Billiard
scheduled daytime naps, in particular in patients who remain profoundly sleepy

despite awakening medication (Rogers et al. 2001).
8.2 Pharmacological
See Table 3.
8.2.1 Modafinil
Modafinil is a wake promoting drug which has transformed the treatment of EDS
associated with narcolepsy. It was identified in 1976, as an active metabolite of
adrafinil, a compound developed as a cognitive enhancer for the elderly (Duteil
et al. 1979). Like many compounds, modafinil was found to be clinically useful
long before its pharmacological target was known. Modafinil was originally
thought to be an alpha-1 adrenergic agonist due to the ability of central alpha-1
antagonists such as prazosin and phenoxybenzamine to antagonize the modafinil-
induced increase motor activity in mice (Duteil et al. 1990) and wakefulness in cats
(Lin et al. 1992). However, preclinical studies have shown that it is not a direct or
indirect alpha-1 adrenergic agonist and experiments in narcoleptic canines have
shown that the compound does not modify canine cataplexy even at doses pro-
moting alertness (Shelton et al. 1995).
Among other potential targets for modafinil were the cell membrane monoamine
transporters. Indeed, at the time when modafinil’s wake promoting effect was dis-
covered, various agents that bind to and inhibit the activity of monoamine trans-
porters, such as cocaine and amphetamines, were known to promote wakefulness.
The first evidence that modafinil binds competitively to a monoamine transporter,
specifically the dopamine transporter (DAT) came in 1994. In vitro, modafinil
competitively displaced the binding of 3H-WIN 35,428, a known DAT ligand, but
Table 3 Medications available for the treatment of excessive daytime sleepiness of narcolepsy
Medication FDA approval EMA approval
Modafinil Yes Yes
Armodafinil Yes No
Dextroamphetamine sulfate Yes No
Methylphenidate Yes Yes (immediate release only)
Selegiline No No
Mazindol No No (yes in France)
Atomoxetine No No
Sodium oxybate Yes Yes
Abbreviations: FDA Food and Drug Administration (in the US). EMA European Medicine Agency
did not displace the serotonine transporter (SERT) and the norepinephrine transporter
(NET) ligand (Mignot et al. 1994). In comparison with other dopamine reuptake
inhibitors such as nomofensine, cocaine, buproprion, the activity of modafinil for the
uptake site was very weak, but the compound was exceptionally selective for the
dopamine transporter (Mignot et al. 1994). Consistent with these data, modafinil
administration increases extra cellular levels of dopamine in brain as measured by
in vivo microdialysis (De Saint-Hilaire et al. 2001), wake-promoting actions are
absent in DAT-knock-out mice (Wisor et al. 2001) and it has been demonstrated, in
positron emission tomography (PET) studies, that modafinil causes the displacement
of the dopamine receptor ligand raclopride and the DAT ligand cocaine in the human
brain (Wolkow et al. 2009). Thus, the awakening effect of modafinil is indeed due to
the dopamine reuptake inhibition.
Nevertheless, modafinil has a number of non dopaminergic effects which include
activation of alpha-1 adrenergic receptors (Duteil et al. 1990), regulation of cortical
serotonergic transmission (Ferraro et al. 2000), inhibition of striato-pallidal GABA
release (Ferraro et al. 1998), increase of glutamate (Ferraro et al. 1997) and histamine
release (Ishizuka et al. 2003). However, these non-dopaminergic effects of modafinil
in vivo may be secondary to elevated extracellular dopamine (Wisor 2013).
Modafinil is available as a racemic mixture of the S and R enantiomers.
Regarding pharmacokinetics, modafinil is absorbed rapidly with a time to peak
concentration of 2–4 h. Approximately 60 % of the drug is linked to plasma pro-
teins and the main metabolic pathway is its transformation into inactive metabolites
at the hepatic level. Those are subsequently eliminated by the kidneys. The elim-
ination half-life is 14–16 h. The steady state is reached after 2–4 days. A limitation
in the use of modafinil is the possibility of induction of some cytochrome P450
(CYP) hepatic enzymes, which may reduce plasma levels of oral contraceptives and
other drugs such as calcium antagonists, statins and cyclosporine.
Modafinil may also inhibit certain CYP hepatic enzymes, with subsequent
increase in the level of some drugs including warfarine, phenytoin, propranolol.
Modafinil was first used to treat narcolepsy and idiopathic hypersomnia, with
unexpected good results, in 1983 (Bastujji and Jouvet 1988). Following further open
label studies, a first multicenter, randomized, placebo-controlled trial was performed
in 50 patients with narcolepsy with cataplexy (Billiard et al. 1994). Modafinil was
administered in a double-blind cross-over design, at a dosage of 300 mg versus
placebo and results judged through questionnaires, sleep log, polysomnography and
maintenance of wakefulness test (MWT). An overall clinical benefit was noted by
physicians as well as a significant improvement of the MWT for patients on mod-
afinil in comparison with placebo (p < 0.05). The adverse effects, headaches, irri-
tability and insomnia mainly occurred at the onset of treatment and were relatively
limited. Modafinil was officially registered for narcolepsy in France, in June 1992,
and was put on the market, also in France, in September 1994.
In June 1993, Cephalon, Inc, licensed the rights to modafinil in the USA from its
French developer in Paris, Lafon Ltd. From that time on, Cephalon conducted
additional preclinical and phase 1 studies on pharmacokinetics and mechanism of
action, while large scale clinical trials were performed. The first one was a class II
244 M. Billiard
evidence study in 70 patients in Canada (Broughton et al. 1994). It showed a

significant decrease in the likehood of falling asleep measured by the Epworth
sleepiness scale (ESS), a reduction of EDS and irrepressible episodes of sleep as
assessed by a sleep log, and a significant improvement in maintaining wakefulness
measured by the MWT, with both 200 and 400 mg/day. The following clinical
studies were two class I evidence studies in 285 and 273 patients respectively,
which showed consistent improvements in a subjective measure of sleepiness, ESS,
and in clinically assessed changes in the patient’s condition, Clinical Global
Impression (CGI), and significant improvement in maintaining wakefulness
(MWT) and in decreasing sleepiness, judged on the MSLT with both the 200 and
the 400 mg doses per day (U.S. Modafinil in Narcolepsy Multicenter Study Group
1998, 2000). Overall modafinil exhibited a favourable adverse event profile, the
most common adverse effects consisting of headache, nausea, nervousness and
rhinitis. The use of modafinil was approved by the Food and Drug Administration
in 1998. Three further studies dealt with open-label extension which showed
positive treatment effects sustained for periods of 40 weeks (Beusterien et al. 1999),
16 weeks (Moldofsky et al. 2000) and 40 weeks (Mitler et al. 2000). As in previous
trials, modafinil was generally well tolerated in these studies; moreover, abuse
potential was low. Finally, a meta-analysis of 1054 patients with narcolepsy
demonstrated that modafinil (200–600 mg) improved EDS relative to placebo,
decreasing ESS, increasing mean sleep latency (MSL) on the MSLT and increasing
MSL on the MWT (Golicki et al. 2010).
Modafinil can be taken in variable doses from 100 to 400 mg/day, in one dose in
the morning or in two separate doses in the morning and in the afternoon. The most
frequently reported adverse effects are headache, nausea and irritability. Headache
generally disappears after a few days of treatment. Other possible adverse effects
include anxiety, insomnia, hyperactivity.
Exceptional cases of serious or life-threatening rashes (Stevens-Johnson syn-
drome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic
symptoms) have been reported in children, in worldwide post marketing experience
(US food and Drug Administration 2007). No modifications in blood pressure have
been observed. The potential for abuse is low. There are approximately 30 % of
dropouts, the majority of which are due to insufficiency or lack of activity.
8.2.2 Armodafinil
In 2007, the R-enantiomer of racemic modafinil was approved by the FDA for the
treatment of EDS associated with narcolepsy. The modes of action of armodafinil
are comparable to those of modafinil. Peak concentration is obtained after 2–4 h.
Armodafinil has an elimination half-life of 10–14 h, whereas the S-enantiomer has
an elimination half-life of 3–4 h. It is approximately twice more potent than
racemic modafinil per mg, once steady state is achieved. Doses of 150 and 250 mg
of armodafinil and placebo were tested in 196 patients with narcolepsy (Harsh et al.
2006). The MWT was the main endpoint. Significant improvements were seen at all
time points for the 150 mg dose, while statistical significance was not reached at 8
and 12 weeks for the 250 mg dose. In contrast to modafinil, armodafinil is taken
once a day. Headache is a common adverse effect, but is usually avoidable by
increasing the dose slowly.
8.2.3 Amphetamines
At low doses amphetamines increase dopamine release and, to a lesser extent, that
of noradrenaline and serotonin. At higher doses they provoke the inhibition of
reuptake and monoaminergic depletion. These effects are mediated by specific
catecholamine transporters, mainly the DAT. The primary action responsible for the
psychomotor stimulant effects appears to be the increased dopamine release
(Nishino and Mignot 1997).
Amphetamines were first used to treat narcolepsy in 1935 (Prinzmetal and
Bloomberg 1935). Both the L- and D-isomers have been used, either in isolation or
as a racemic mixture. The D-isomer is slightly more potent and is more generally
used, at a dose of 5–60 mg a day. The elimination half-life is 16–30 h depending on
the isomer. Adverse effects include increased heart rate and blood pressure, pal-
pitations and sweating (Mitler 1994). Increased anxiety may occur in predisposed
patients. Mood may be temporarily enhanced. Higher than recommended doses
(60 mg/day) may precipitate psychosis (Auger et al. 2005). Tolerance to
amphetamines may develop in one-third of patients (Guilleminault 1993).
Amphetamines can be addictive, although there is little or no evidence of abuse and
addiction in narcoleptic patients (Parkes and Dahlitz 1993).
8.2.4 Methylphenidate
Methylphenidate is primarily a DAT reuptake inhibitor, but it has also been shown
to increase dopamine release (Leonard et al. 2004). Methylphenidate is not fully
specific for dopamine transmission, also affecting more mildly other monoamines.
Methylphenidate is transformed into an inactive metabolite at the hepatic level,
which in turn is eliminated by the kidneys. Onset of action after oral administration
is 20 min, duration of action approximately 3 h and elimination half-life 6 h.
Methylphenidate was introduced for the treatment of narcolepsy in 1953 (Yoss
and Daly 1959). The usual daily dose is 10–60 mg a day. A study assessing
objectively the efficacy of methylphenidate, pemoline and protriptyline in nar-
coleptic patients showed that methylphenidate significantly improved the ability to
stay awake in comparison with the two other drugs (Mitler et al. 1986). Adverse
effects are the same as with amphetamines, but less frequent and less intense.
246 M. Billiard
8.2.5 Selegiline
Selegiline is a potent irreversible MAO-B selective inhibitor which acts mainly by

inhibiting catabolism of dopamine. In addition it is metabolically converted into
desmethyl selegiline, amphetamine and methamphetamine. The elimination
half-life of the main metabolites is variable, 2.5 h for desmethyl selegiline, 18 h for
amphetamine and 21 h for methamphetamine.
The efficacy of selegiline has been proven in two class 1 evidence studies, in
which it was shown that dosages of 10–40 mg/day reduced significantly EDS and
sleep attacks (Hublin et al. 1994; Mayer and Meier-Ewert 1995).
Use of selegiline is limited by potentially sympathomimetic adverse effects and
interaction with sympathomimetic drugs (methylphenidate, amphetamines, nasal
decongestants). Co-administration of triptans and serotonin specific reuptake inhi-
bitors is contraindicated. Special attention to the diet is warranted; it must be low in
tyramine.
8.2.6 Mazindol
Mazindol is an imidazoline derivative which has been developed as an anorectic

drug. It acts as a weak dopamine-releasing agent, but it also blocks dopamine and
norepinephrine reuptake. Mazindol has a high affinity for the dopamine and
norepinephrine transporters (Nishino and Mignot 1997).
The plasma peak concentration is reached after 2–4 h and the elimination
half-life is 33–55 h.
Mazindol was first used for narcolepsy in 1975, with good results on the number
of daily sleep attacks and cataplexy (Parkes and Schachter 1979). The most com-
mon adverse effects are dry mouth, palpitation, anorexia, nervousness and head-
aches. Rare cases of pulmonary hypertension and valvular abnormalities have been
reported and the drug has been withdrawn from the market in most countries. Of
note, in a recent retrospective analysis conducted in France in patients with nar-
colepsy, idiopathic hypersomnia and symptomatic hypersomnia, under mazindol
(1–6 mg) for an average of 30 months, the ESS decreased from 17.7 ± 3.5 to
12.8 ± 5.1, with an average fall of −4.6 ± 4.7 (Nittur et al. 2013).
8.2.7 Atomoxetine
Atomoxetine is a specific adrenergic blocker used in attention deficit hyperactivity

in children and adolescents (Garnock-Jones and Kerting 2009). It is a weak stim-
ulant and it has been proposed in the treatment of narcolepsy (Niederhofer 2005).
Common adverse effects include headache, abdominal pain, decreased appetite,
nausea, vomiting. It is useful for patients at risk of substance abuse.
8.2.8 Sodium Oxybate
Sodium oxybate, the sodium salt of gamma-hydroxybutyrate, is a very potent

inhibitor of cataplexy (U.S. Xyrem Multicenter Study Group 2004) but is also
effective in reducing EDS (Black and Houghton 2006). Thus, sodium oxybate is the
only medication that can treat all the symptoms of narcolepsy. The mode of action
is unclear, but sodium oxybate activates the gamma-aminobutyric acid receptor
type B (GABA-B receptor) (Maitre 1997). However, because the compound has a
very low affinity/low potency on the GABA-B receptor and has differential effects
across species, it is very difficult to demonstrate whether or not the GABA-B effect
is sufficient for the therapeutic effects in narcolepsy (Mignot 2012). Sodium oxy-
bate is rapidly absorbed following oral administration. Plasma peak concentration is
reached within 25–75 min of ingestion.
Four class 1 evidence studies have shown reduced excessive daytime sleepiness,
increased levels of alertness and ability to concentrate (US Xyrem Multicenter
Study Group 2002, 2003; Mamelak et al. 2004; The Xyrem International Study
Group 2005), and a later study showed sodium oxybate and modafinil to be equally
efficient for the treatment of excessive daytime sleepiness (Black and Houghton
2006). The usual starting dose is 4.5 g/night, divided into two equal doses of
2.25 g, the first one at least 2 h after eating and the second one 3–4 h later. As the
dose of 4.5 g is generally only partially effective, the dose must be gradually
increased by 1.5 g steps every week with weekly consultation. Titration to effect is
a critical component of patient management with sodium oxybate. Full therapeutic
benefit generally occurs at the 6–9 g/night doses. Most commonly reported adverse
effects are nausea, which usually vanishes after a few days, loss of appetite, noc-
turnal enuresis which may persist intermittently, confusional arousals and headache.
Of concern is abuse potential. Indeed, sodium oxybate is misused in athletes for its
metabolic effects (growth hormone releasing effect) and it has been used as a “date
rape” drug because of its rapid sedating effects. However, safety overview of
postmarketing and clinical experience of sodium oxybate revealed that the drug has
a low risk in narcoleptic patients when used properly (Wang et al. 2009).
9 Recommendations
Behavioral treatment measures are always advisable. Because of varying perfor-

mance demands and limitations on work or home times for taking them, naps are
best scheduled on a patient-by-patient basis.
First-line pharmacological treatment of EDS and irresistible episodes of sleep is
traditionally modafinil because of its efficacy and safety. It is given in two doses,
100 mg in the morning and 100 mg at noon. The daytime dose may be increased up
to 400 mg but not further. If headaches occur, temporary adjustment of the dose is
advisable. Experience shows that modafinil is effective in around 60 % of patients.
248 M. Billiard
When modafinil is uneffective, addition of sodium oxybate is advisable as the

combination of the two compounds is often more effective than each drug alone
(Black and Houghton 2006). However, in the case of narcolepsy type 1, narcolepsy
with hypocretin deficiency, sodium oxybate may be considered as first line treat-
ment of EDS, given its activity on both EDS and cataplexy and its possible
superiority to modafinil in treating EDS in these patients (Mignot 2012).
Methylphenidate is of interest because of its short elimination half-life allowing
its use on an on-demand basis.
As some patients respond better to mazindol than to any other drug, the use of
the drug may still be considered, provided that the treatment is closely monitored.
Finally, other compounds may sometimes be prescribed in case of failure of all
other drugs.
As there is no cure for narcolepsy and as patients require long term management,
it is of utmost importance that patients should be regularly evaluated and encour-
aged to continue their treatment.
At present, medications used to treat children or adolescents have shown efficacy
mostly based on clinical experience, given the lack of level 1 evidence based
studies in the pediatric population. Therefore, most compounds used in adult nar-
colepsy are prescribed off label in pediatric patients (Lecendreux 2014).
In elderly patients sodium oxybate is not recommended because of its high salt
content.
For women of childbearing age taking modafinil, it is recommended to take a
contraceptive containing at least 50 lg ethinyloestradiol, due to the possible
increase metabolism of oral contraceptives.
Although there is no evidence of teratogenicity with the drugs currently used in
narcolepsy (Thorpy et al. 2013), these should ideally be discontinued during
pregnancy. However, in most cases this is not possible, but a dose reduction should
be encouraged.
10 Novel Therapies Under Development
Pitolisant is a potent and highly selective non-imidazole inverse agonist at the

recombinant human H3 receptor (Ligneau et al. 2007). It was tested according to a
double blind, randomized, parallel group control trial, in 95 patients with nar-
colepsy (Dauvilliers et al. 2013). Efficacy endpoint was ESS. Pitolisant was
superior to placebo in reducing ESS. It was well tolerated in comparison with
modafinil.
JZP-110, formerly known as ADX-N05, is a phenylalanine derivative which
indirectly enhances dopaminergic and noradrenergic transmission (Hasan et al.
2009). It was recently tested, according to a randomized, double-blind,
placebo-controlled trial of crossover design, in 33 narcoleptic patients (Bogan et al.
2015). Efficacy endpoints included MWT sleep latency and ESS. Efficacy was
observed at 150–300 mg/day and as early as one week after initiating treatment.
JZP-110 was generally well tolerated. The most common adverse effects were
nausea, non cardiac chest discomfort and headache.
Based on the increased evidence that narcolepsy is of autoimmune origin,
individual patients have been given intravenous immunoglobulins close to disease
onset (Dauvilliers 2006; Knudsen et al. 2010). Beneficial effects have been claimed.
However these studies included a limited number of patients and were not blinded.
Finally, hypocretine receptor agonists are very attractive from a theoretical point
of view. Unfortunately, the hypocretin peptide does not cross the blood brain
barrier. However, some limited success have been obtained with hypocretin ago-
nists administered via the intranasal route (Baier et al. 2011).
11 Conclusion
Narcolepsy, particularly excessive daytime sleepiness, is a long standing condition.

Modafinil was a major advancement in the treatment of excessive daytime sleepi-
ness of narcoleptic patients when it was launched in the 1990s. Today, due to its
efficacy and safety, it is still the first line treatment of excessive daytime sleepiness.
Yet, sodium oxybate, either in combination with modafinil or alone, is of major
interest and may even be of more value in the treatment of EDS in narcolepsy type
1. Other compounds are either open to adverse effects or less efficient, but may be
of interest in patients not responding to either modafinil or sodium oxybate. In
addition, new treatments are currently being tested, which, it is hoped, will add to
the present therapeutic arsenal.
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Long-Term Management Problems
in Restless Legs Syndrome (RLS)/
Willis-Ekbom Disease (WED)
Sudhansu Chokroverty
Abstract Long-term consequences of drug treatment of restless legs syndrome

(RLS) poses a serious challenge for the clinicians because of vexing undesirable
side effects, which compromise the efficacy of treatment and force some patients to
discontinue medication. This chapter addresses these long-term consequences to
RLS treatment, which could be both disease-related and medication-related issues.
In addition, this chapter briefly discusses how to manage or minimize these issues,
and alternative treatment for intractable and refractory cases of RLS.

Keywords Augmentation Opioid-induced hyperalgesia (OIH) Impulse Control

Disorder (ICD) Tolerance Dependence Drug diversion Rebound Sleep

attacks Opioid use disorder (OUD) Ventral tegmental area (VTA)
1 Introduction
There are four major problems for any discussion about long-term consequences of
drug treatment of RLS/WED: 1. Inadequate knowledge about the natural history of
untreated RLS and the incidence of the disease. Is it a chronic progressive disease or
does it ever remits completely? 2. Incomplete knowledge about long-term conse-
quences of the disease itself. 3. Long-term vexing consequences could be both
disease-related and medication-related; and 4. Incomplete knowledge about individual
variation and demographic characteristics (some of these could be genetically deter-
mined). Despite these problems it is not only relevant but is also necessary to have a
basic fundamental knowledge about long-term consequences of RLS and long-term
management issues to address these adequately and use alternative treatments for
S. Chokroverty (&)
NJ Neuroscience Institute at JFK, Edison, NJ, USA
e-mail: schokroverty@jfkhealth.org; schok@att.net
S. Chokroverty
Robert Wood Johnson Medical School, New Brunswick, NJ, USA

DOI 10.1007/978-3-319-46437-4_12
256 S. Chokroverty
intractable and refractory cases of RLS/WED. This chapter addresses both

disease-related and long-term management issues in RLS.
2 Diagnostic Criteria, Prevalence and Incidence

of RLS/WED
RLS/WED is a sensorimotor neurological movement disorder with an unknown natural

history causing profound impairment of sleep and quality of life. There is not a single
diagnostic laboratory test, however there are five essential criteria all of which are
required for making a diagnosis (Allen et al. 2014) (see Box 1). In addition, there are
specifiers for clinical course (e.g., chronic persistent RLS with symptoms occurring in
untreated patients at least twice weekly for the past year, and intermittent RLS with
symptoms occurring less than two days per week, and with at least five lifetime events),
and specifiers for clinical significance (e.g., causing significant distress impairing social,
personal and occupational interaction). These specifiers as well as supporting features
(e.g., a positive family history, a positive response to dopaminergic medication, and the
presence of periodic limb movements [PLMS] during polysomnographic [PSG]
recording) are not required for diagnosis.
The overall prevalence of RLS in epidemiological studies of the North American
and European populations (Allen et al. 2005) was estimated at 7.2 % in adults (when
severity was not considered) with slightly lower rates estimated in some Asian coun-
tries (Tan et al. 2001), suggesting the possibility of environmental and racial influence
on the disease. The prevalence, however, was estimated at 2.7 % when clinical sig-
nificance and frequency (occurring twice a week or more) were considered, whereas the
prevalence decreased to 0.8 % with high impact of symptoms on patient’s life (Allen
et al. 2010). The incidence and natural history of RLS/WED have not been studied
adequately. Three recent studies have reported a cumulative incidence of 8 %
(Szentkiralyi et al. 2011) and 6.6 % (Budhiraja et al. 2012), and a persistence of
symptoms of 40 % (i.e., 60 % remitters) (Kagimura et al. 2011) over a two-year period
suggesting marked variability in RLS symptoms, however, these findings remain
controversial. RLS is often unrecognized and undiagnosed. There is a female pre-
ponderance and the age at which patients seek medical advice ranges between 40 and
60 years. The onset of the disease, can, however, occur from infancy to old age. The
pathophysiology of RLS/WED remains undetermined. The disease may be idiopathic
(primary) or comorbid with other medical and neurological disorders. There are mul-
tiple and inconsistent theories for its causation, but the most popular theory centers
around an iron-dopamine connection, with problem in iron acquisition in the basal
ganglia, which in term causes dopamine dysfunction (Allen 2013).
Long-Term Management Problems in Restless Legs … 257
3 Long-Term Management Decisions
A spectrum of pharmacologic treatment options in addition to non-pharmacological

therapy is available (Box 2) to treat RLS/WED patients presenting with symptoms of
variable frequency and severity (Allen 2013). Since EKbom’s lucid description of the
entity in 1945 (Ekbom 1945) which is known today as Restless Legs Syndrome (RLS)/
Willis-Ekbom disease (WED) and recognition of its symptoms in English literature by
Willis in (Willis 1685) no satisfactory treatment emerged until the serendipitous
observation by Akpinar (Akpinar 1982) of the benefit of Levodopa for RLS. Since then
dopamine agonists have remained the first-line therapy for this condition until recently.
Many short-term (up to three months) (Partinen et al. 2006; Winkelman et al. 2006;
Trenkwalder et al. 2004, 2006a; Oertel et al. 2007; Allen et al. 2004; Bliwise et al. 2005;
Walters et al. 2004; Bogan et al. 2006) and a limited number of long-term (6–12 months
or more) clinical trials have attested to their efficacy (Trenkwalder et al. 2006a, 2008;
Hogl et al. 2009; Montplaisir et al. 2006a, b; Hening et al. 2010; Silber et al. 2003; Ondo
et al. 2004; Garcia-Borreguero et al. 2002, 2007, 2008; Clavadetscher et al. 2004; Inoue
et al. 2010; Lipford and Silber 2012; Oertel et al. 2011). Fourteen years after Akpinar’s
(1982) observation of beneficial effect of levodopa treatment in RLS it was found out
that all was not well. Researchers from Johns Hopkins University in (Allen and Earley
1996) observed very undesirable long-term iatrogenic side effects of dopaminergic
medications causing worsening of RLS Symptoms, which they called “augmentation”.
These symptoms are the most significant vexing long-term consequences of dopamin-
ergic treatment besides other long-term consequences some of which are disease-related
(see further on). Although a large percentage of patients (up to 73 %) on levodopa
treatment developed augmentation, it was also noted with dopamine agonist
(DA) treatment but to a lesser extent. It is important to be aware of the consequences as
these can be managed, minimized, or prevented by following appropriate principles of
treatment. The undesirable long-term consequences of dopaminergic treatment provided
an impetus for researchers to find alternative treatments as well as to look for other
long-term consequences including the long-term course (natural history) of RLS/WED.
Before discussing long-term treatment-related consequences of RLS, I would like to
briefly summarize evidence-based and consensus-based recommendations for the
long-term pharmacologic treatment of RLS/WED developed by the Task Force
appointed by the International Restless Legs Syndrome study Group (IRLSSG) based on
a review of 61 papers published. Using a modified evidence-grading scheme the Task
Force (Garcia-Borreguero et al. 2016) recommended the following guidelines: 1.
Pregabalin is effective for up to one year (Level A evidence) whereas pramipexole,
ropinirole and rotigotine patch are effective for up to six months in treating RLS (Level A
evidence); 2. Gabapentin enacarbil, pramipexole, and ropinirole up to one year, and
rotigotine up to five years are probably effective (Level B); 3. Ergoline dopamine agonists
(pergolide, bromocriptine and cabergoline) should not be used in treating RLS/WED
because the risks (particularly cardiac valvulopathy and fibrosis) out-weigh the benefits,
and 4. Other pharmacologic agents (see Box 2) have insufficient evidence for long-term
treatment of RLS/WED. The Task Force strongly recommended (Garcia-Borreguero
258 S. Chokroverty
et al. 2016) either alpha-2-delta calcium channel ligand or a dopamine-receptor agonist as

the first-line treatment for most RLS/WED patients depending on the severity of
symptoms, comorbid conditions, and cognitive status. The Task Force also identified
serious gaps in knowledge about long-term treatment options and outcomes, drug
combination trials, evaluating dose of opioids, animal and biological models of RLS and
augmentation. Finally, the Task Force recommended more studies to meet the long-term
treatment needs of patients with RLS. The Task Force, however, failed to make any
recommendations about drug holidays or drug rotations. In addition, three evidence based
practice parameters for management of RLS are published by the American Academy of
Sleep Medicine (Chesson et al. 1999; Littner et al. 2004), and the European Federation of
Neurological Society (Vignatelly et al. 2006).
4 Long-Term Consequences
The long-term management of RLS/WED poses a serious challenge for the clini-
cian because of the emergence of long-term undesirable side effects (Box 3 and
Box 4), which compromise the efficacy of treatment and force some patients to
discontinue medication (Chokroverty 2011). Long-term consequences of manage-
ment can be broadly divided into two categories:
1. Disease-related and 2. Medication related (see Boxes 3 and 4), issues
A. Disease-related issues
I. Impact of RLS on Sleep and Its Consequences

Sleep disruption, although not listed as an essential or supportive feature, is a very
common complaint for which RLS patients seek help from their physicians. In the
REST study by Hening et al. (2004) approximately 69 % of those with moderate to
severe idiopathic RLS patients took more than 30 min to fall asleep (sleep onset
insomnia) and 60 % woke up three or more times at night (Sleep maintenance
insomnia). Several other authors reported similar findings (Montplaisir et al. 1997;
Cuellar et al. 2007). These symptoms severely impacted their quality of life. In a
recent epidemiological study (Ohayon et al. 2010), those who wake up in the
middle of the night and have difficulty falling asleep within 15 min complain of
impaired attention and concentration, and fatigue in the daytime. Sleep difficulty
may also be responsible for cognitive deficits noted in some RLS patients (Pearson
et al. 2006).There are a limited number of PSG studies to characterize sleep in RLS
patients (Hornyak et al. 2007; Saletu et al. 2002; Winkelman et al. 2009; deWeerd
et al. 2013; Ferri 2012). Hornyak et al. (2007) documented prolonged sleep onset
latency, decreased sleep efficiency (SE), and sleep fragmentation as compared with
controls in 45 out of 100 consecutively identified moderately severe RLS patients
with a mean international Restless Legs Syndrome study group score (IRLS) of
24 ± 6.2 and an equal number of age-and sex-matched healthy controls. Their

other significant finding was reduced REM sleep percentage in RLS patients which
may be responsible for hyperalgesia in these patients as demonstrated by the
presence of mechanical but not static hyperalgesia in RLS patients (Montplaisir
et al. 2006). In contrast, in a small study involving 12 RLS patients Saletu et al.
(2002) found decreased REM density but normal sleep onset latency and SE.
Winkelman et al. (2009) analyzed unattended in-home PSG data in 2971 subjects
out of 3433 patients included in the sleep Heart Health Study (SHHS), a population
and cross-sectional observational study. These authors found increased mean sleep
latency and arousal index in RLS patients compared to those without RLS but did
not find any difference in sleep stage percentages. Other PSG studies also found
sleep fragmentation with increased arousal and fragmentation index in RLS
patients (Hening et al. 2010; Silber et al. 2003). Two recent reports on transcranial
magnetic stimulation (TMS) evaluating cortical excitability in patients with RLS,
obstructing sleep apnea syndrome (OSAS), chronic insomnia, and healthy subjects
with sleep deprivation (SD) and sleep fragmentation (SF) showed distinctive
physiological differences in cortical excitability in these subjects (Lanza et al. 2015;
Scalise et al. 2014). In chronic insomnia and sleep deprived healthy subjects Lanza
et al. (2015) after literature review reported an imbalance in intracortical inhibition
and excitation favoring an “activating” pattern whereas RLS patients had markedly
reduced intracortical inhibition, but intracranial facilitation was normal or
increased. Experimental study by Scalise et al. (2014) shown no significant dif-
ference in motor evoked potential (MEP) amplitude, intracortical inhibition and
post-exercise MEP facilitation before and after sleep fragmentation in healthy male
subjects. Based on previous TMS findings of decreased intracortical inhibition in
RLS patients by these authors and others they (Scalise et al. 2014) speculated that
SD and SF are two different phenomena, and that SF in RLS is different from SD
and SF in healthy subjects, and alterations in cortical excitability in RLS are
intrinsic to the underlying disease and not directly related to SF present in RLS.
It is interesting to note that despite SF, a large number of RLS patients do not
complain of excessive daytime sleepiness (EDS). In the REST study (Hening
et al. 2004) only 6 % of patients complained of EDS. One report (Allen et al.
2002) suggested that a hyperalert state could be due to increased cerebrospinal
(CSF) hypocritin-1 (orexin-A) in RLS patients but this report was contradicted
by a later report (Stiasny-Kolster et al. 2003). Also magnetic resonance spec-
troscopic (MRS) study of brain (Allen et al. 2013) showed evidence of
excessive thalamic glutamate explaining in part the hyperarousal state, but this
was contradicted by a later report (Winkelman et al. 2014). In contrast, several
studies documented EDS in up to 38 % of RLS patients (Budhiraja et al. 2012;
Ulfberg et al. 2001; Winkelman et al. 2006; Fulda and Wetter 2007). In any
case most of the patients complain of impairment of daytime vigilance, atten-
tion and concentration, but not daytime sleepiness. Furthermore, when sleepi-
ness is documented in RLS patients, it is disproportionately less severe
considering the degree of sleep disruption observed in these patients (Fulda and
260 S. Chokroverty
Wetter 2007; Kushida et al. 2004). In summary, a significant disease-related

long-term consequence is its impact on sleep, and the resulting consequences
which have neither been addressed adequately nor controlled by medications.
Many RLS patients are left with chronic insomnia despite improvement or
resolution of their RLS symptoms. Chronic sleep deprivation in theory may be
associated with increased cardiovascular morbidity, impaired glucose tolerance,
insulin resistance, obesity, inadequate concentration and attention, anxiety and
depression, decreased long-term potentiation (LTP) causing impaired cognition
and motor learning. Some RLS patients may complain of “sleep attacks”,
meaning sudden onset of sleep without any warning. These are thought to be
mostly related to dopaminergic medication (See further on), but may be
intrinsic to the disease itself.
2. Burden and course of the disease—Impaired health and quality of life
RLS has significant long-term consequences on health and quality of life (Allen
et al. 2005; Cho et al. 2012; Abetz et al. 2004). Studies using medical outcomes
short-form (SF-36) [physical functioning, general health, bodily pain, vitality,
social functioning, and emotional health] in RLS patients have shown poor
health-related quality of life. This impaired quality of life is comparable to that
shown in other chronic medical illnesses (e.g., diabetes mellitus, hypertension,
osteoarthritis, congestive heat failure (Abetz et al. 2004). RLS is probably a chronic
progressive disease (Allen 2013) (although we do not quite know the natural
history of this illness; one report shows remission or disappearance of symptoms in
up to 60 % of cases (Kagimura et al. 2011)) with cumulative burden contributing
to impaired health and quality of life. One question that has not been resolved in
the causation of this impaired quality of life is the role of sleep disruption. It is
plausible that most of the long-term consequences as shown in cross-sectional
studies (See further on) may have been related to chronic sleep fragmentation and
disruption (Allen 2013; Kushida et al. 2004; Hening et al. 2004).
3. Acute Exacerbation and “Break though” RLS Symptoms
An important and often unexplainable log-term problem is an acute exacerbation of
RLS symptoms occurring intermittently which may be due to associated iron
deficiency, comorbid conditions and lifestyle changes (e.g., inactivity), or due to
ingestion of some non-RLS medications (e.g., antidepressants, antihistamines and
anti-nausea drugs) (Allen 2010). After a period of satisfactory relief of symptoms,
patients may observe that despite continuing the RLS medication there is exac-
erbation of RLS symptoms lasting for minutes to hours. These symptoms are
commonly seen in moderate to severe RLS patients impacting quality of life. These
aggravating symptoms may occur spontaneously or as “breakthrough” manifes-
tations (unexpected and sudden) which are often precipitated by quiescence
(Tzonova et al. 2012). The prevalence of these “break through” symptoms is
related to duration of the disease and not to treatment. The question whether this is
the beginning of augmentation or just disease progression remains unsettled. If
associated iron deficiency is found (e.g., low serum iron or serum ferritin below
50–70 ng/ml), this needs to be treated with iron sulphate along with vitamin C to
promote absorption. In addition, the cause should be investigated. In many women

this is due to excessive menstrual blood loss, but in absence of any obvious cause,
gastrointestinal causes such as colonic cancer should be excluded. Lifestyle
changes such as partial retirement, relative inactivity and sleep deprivation may
also be responsible for these acute or “break through” symptoms. Comorbid
medical conditions may also cause exacerbation of RLS symptoms. In the post-
operative period RLS symptoms may be exacerbated, particularly after discon-
tinuation of analgesics and opiates. Finally medication status should be reviewed.
Antidepressant medications (e.g., selective serotonin reuptake inhibitors [SSRIs],
selective serotonin and norepinephrine reuptake inhibitors [SSNRIs], and
over-the-counter (OTC) medications (e.g., antihistamines and anti-nausea drugs)
often exacerbate RLS symptoms. Rare cases of RLS may present with severe
almost continuous symptoms throughout the day like “RLS Status” requiring
epidural morphine administration (Vahidi et al. 1994).
4. Depression and Anxiety
RLS patients are at increased risk of having anxiety and depression, particularly
generalized anxiety and panic disorders, and major depression (Winkelmann
et al. 2005). In fact the 19th Century physician Wittmaack in 1861 described
RLS-like symptoms under the title of “anxietiastibiarum”. Most likely chronic
insomnia of RLS is responsible for associated (comorbid) anxiety and
depression rather than intrinsic to the disease.
5. Cardiovascular Consequences
The most controversial and hotly debated topic is the question of an association
between RLS and cardiovascular disease including stroke and hypertension.
Many cross sectional studies and surveys suggested such an association but
causality is not proven (Winkelman et al. 2006, 2009; Schlesinger et al. 2009;
Ulfberg et al. 2001; Walter and Rye 2009; Cuellar and Ratcliffe 2008). There
are, however, several reports contradicting these association (Szentkiralyi et al.
2013; Winter et al. 2012, 2013; Hogl et al. 2005). Variable study design and
definitions of RLS as well as inadequate consideration of confounding factors
may explain these inconsistent results. Some of the confounding factors which
should be considered include sleep duration and schedule, obesity, smoking
habits, alcohol consumption, lifestyle factors (e.g., exercise, inactivity), lipid
profile, premorbid hypertension and diabetes mellitus (type 2), socioeconomic
status, ethnicity, medication and other comorbid conditions. What is needed is
longitudinal study including large number of patients addressing all these
confounding and risk factors with prolonged follow-up to adequately answer
this question of association. At present there is no convincing and compelling
evidence for RLS/WED being responsible for cardiovascular catastrophe
including stroke and hypertension. As stated above it is plausible that most of
these associations may be explained by chronic sleep impairment caused by
RLS (Cosentino et al. 2012; Allen and Earley 2000).
262 S. Chokroverty
B. Medication Related Issues (see Box 4)
I. Long-Term Consequences related to dopaminergic medications

1. Augmentation, an iatrogenic side effect (Box 4) is the most serious
medication-related issue in RLS.
As mentioned above the term augmentation was introduced by Allen and Early
in (Allen and Earley 1996) to describe an iatrogenic complication of levodopa
treatment characterized by worsening of symptoms after treatment is started. These
authors described intensification of RLS symptoms with increasing levodopa dose
and duration of treatment in 73 % of patients requiring a change of treatment in
50 % of patients. Since then, it has become evident that dopamine agonists
(DA) can also be associated with augmentation but to a less extent. In one study,
treatment with pramipexole (a dopamine agonist) was associated with an annual
rate of augmentation of about 7 % over a 10-year period suggesting a slow pro-
gression of dopaminergic dysfunction with continuing treatment (Silver et al.
2011). The prevalence of augmentation after long-term dopaminergic treatment
varies widely because of the absence of a set of diagnostic criteria until recently (see
Box 5). Augmentation is noted so far exclusively with dopaminergic medications,
more so with those having shorter than intermediate or longer half life (Oertel et al.
2011; Trenkwalder et al. 2006b). There are however, two reports with tramadol
(Earley and Allen 2006; Vetrugno et al. 2007) under the label of augmentation
which actually are consistent with opioid-induced hyperalgesia (see further on) that
resembles augmentation clinically but develops through a different mechanism.
i. Prevalence of augmentation
Augmentation is reported in 27–82 % of patients on long-term levodopa,
8–56 % on long-term pramipexole, (Winkelman and Johnston 2004; Ferini-Strambi
2002; Silber et al. 2003) 2.3 % on long-term ropinirole (Garcia-Borreguero et al.
2008, 2013) 3–9 % on cabergoline (Trenkwalder et al. 2007; Stiasny-Kolster et al.
2004; Benes et al. 2004), and 2.7–13 % on rotigotine patch (Oertel et al. 2011;
Trenkwalder et al. 2006b; Liu et al. 2016). Liu and coinvestigators (Ondo et al.
2004) recently reported an overall augmentation rate of 5.6 % in primary RLS
patients based on a meta-analysis of 60 studies involving 11,543 participants.
Augmentation was observed in 27.1 % of levodopa-treated patients, 6.0 % of those
treated with DAs, and 0.9 % of those taking pregabalin or gabapentin. The aug-
mentation incidence was 6.1 % for long-term treatment. In a six-month study of
RLS patients on levodopa (Hogl et al. 2010) augmentation occurred progressively,
showing a rate of 60 % at six months causing a drop out in 11.7 %. In that study
median time to occurrence of augmentation was 71 days. In a multicenter European
study of pramipexole (Hogl et al. 2011), six-month incidence of confirmed aug-
mentation was 9.2 %. Although rotigotine patch is thought to have a low risk of
augmentation in a 2008 report (Baldwin and Keating 2008), the authors suggested
that further evaluations are needed.
ii. Definition of Augmentation
The current definition of augmentation includes the National Institute of Health
(NIH) 2002 workshop (Allen et al. 2003) criteria which were later refined in a
WASM (World Association of Sleep Medicine)—IRLSSG—MPI (Max Planck
Institute) Consensus Conference in 2006 and published a year later
(Garcia-Borreguero et al. 2007) (Box 5). An augmentation severity rating scale
(ASRS) specifically designed to measure the severity of augmentation for clinical
trials has been subsequently developed and validated (Garcia-Borreguero et al.
2007). Briefly, augmentation is suspected when symptoms occur 2–4 h earlier than
when the medication was initially started, symptoms are more intense than before,
increasing drug dose is needed prior to developing earlier and more intense
symptoms, and RLS symptoms spread to other body parts (e.g., arms). Other
features of augmentation include shorter latency of onset of symptoms during
quiescence, decreased duration of efficacy of medication, and a paradoxical
response to drug (i.e., increasing the dose will enhance the symptoms while
decreasing the dose will decrease the intensity of symptoms which may take a few
days to few weeks because of drug withdrawal syndrome).
iii. Factors Predisposing to Augmentation
There are several factors predisposing to development of augmentation as listed
below (Box 6): Dose, duration and severity of symptoms, (Hogl et al. 2011; Allen
et al. 2014; Garcia-Borreguero et al. 2016) half-life of medication, iron deficiency,
(Frauscher et al. 2009; Trenkwalder et al. 2008) a positive family history of RLS
(Ondo et al. 2004; Sonka and Kemlink 2004), and individual patient characteristics
(to explain absence of augmentation in most of the RLS patients on dopamine
agonists).
iv. Conditions Mimicking Augmentation
a. Disease progression or “break through” symptoms
Augmentation symptoms may fluctuate in course of time resembling acute
exacerbation, “break through” symptoms or natural progression of the disease
(Garcia-Borreguero et al. 2016) (see above in section A-3). RLS is considered to be
a chronic disease which shows rapid progression if the age of onset is after 45 years
but slow progression in earlier onset patients who are more likely to have a positive
family history (Allen and Earley 2000). In patients with disease progression any
reduction of medication dose will make the symptoms worse and not better in
contrast to symptoms of augmentation which will decrease with dose reduction but
will increase with increasing dose (See above). In addition, disease progression is
usually slow except for acute exacerbations or “break through” symptoms as dis-
cussed previously. On the other hand, augmentation could be dramatic with sudden
worsening of symptoms.
264 S. Chokroverty
b. Akathisia
The most severe form of augmentation may resemble akathisia, a condition
usually seen after ingestion of neuroleptics and hence it is known as
neuroleptic-induced akathisia (NIA) (American College of 1973). However, it
is interesting to note that the term akathisia was introduced by Czech physician,
Haskell in 1911 (Haskovec 1901) when neuroleptic medications were not
known to exist. NIA is characterized by an inner sense of generalized rest-
lessness with forced walking (“tasikinesia”) and other motor manifestations.
Patients cannot stand or sit still and are in constant motion. These movements
are present throughout the day and night, and may become worse in the evening
without any circadian pattern. Severe augmentation has all these features
including loss of circadian pattern, and lack of any relief from movements.
Patients with akathisia, however, have a history of exposure to neuroleptics,
may have mild extrapyramidal findings on examination, less PLMS and sleep
disruption than in augmentation. Finally, the inner restlessness of akathisia is
different from limb restlessness of augmentation.
c. Rebound
This refers to the end of-the-dose effect of dopaminergic drugs with short
half-lives (e.g., levodopa). Symptoms reappear in the early hours of the
morning (e.g., 3–4 a.m.) when blood levels fall. In contrast, augmentation
occurs in the afternoon or early evening, but not in the early morning.
Symptoms do not become more intense in rebound and after an initial period of
exacerbation patients remain symptom-free later in the morning. In augmen-
tation symptoms persist and may expand to other body parts; these do not occur
in rebound.
d. Tolerance
Many patients after responding satisfactorily initially require increasing doses
of dopaminergic medication for relief of symptoms due to wearing off of the
drug as a result of down regulation of dopamine receptors. This is known as
tolerance. It has been suggested that augmentation may go through a stage of
tolerance (Winkelman and Johnston 2004) which should serve as a warning
sign of augmentation (Allen 2013). In contrast to augmentation tolerance does
not cause increasing intensity of symptoms nor does it cause extension of
symptoms to other body parts.
v. Suggested (hypothetical) Mechanisms of Augmentation

The mechanism of augmentation is not known but there are some hypothetical
suggestions not based on valid scientific data (Box 7). It has been suggested that
augmentation is a hyperdopaminergic state caused by over stimulation of
dopamine D1 receptors (excitotoxicity) compared with D2 receptors (Paulus and
Trenkwalder 2006), which may desensitize the receptors (receptor down regu-
lation). One theoretical possibility (not on valid scientific evidence) is excessive
orexinergic (hypocretinergic) stimulation via widespread anatomical projections
to the entire CNS including brain stem and spinal motor neurons causing a
hypermotor syndrome (resembling augmentation). In fact, there is one report of
increased cerebrospinal fluid (CSF) hypocretin-1 levels in evening CSF samples
(Allen et al. 2002) obtained from RLS patients, but these findings have been
contradicted by a later report (Stiasny-Kolster et al. 2003). Another speculative
hypothesis not based on scientific data is dopamine receptor supersensitivity
(which completely contradicts receptor subsensitivity theory) based on the old
tardive dyskinesia theory of Klawans. Another possibility is an imbalance
between dopamine (excess) and acetylcholine (relative deficiency) in the basal
ganglia. Some suggested neural pathways possibly involved in explaining the
occurrence of augmentation (Box 8) include ventral tegmental area with its
connection to nucleus accumbens, diencephalo-spinal pathway, and both pre-
and post-synaptic dopamine receptor pathways.
vi. Treatment of Augmentation

IRLSSG recently published treatment guidelines based on expert opinion and
consensus (Garcia-Borreguero et al. 2016).
Step 1. The first step is to promote the most effective preventive strategy for
augmentation. This means that one should start treatment with low dose and
increase gradually to the lowest effective dose with maximum benefit for RLS
symptoms, and minimal or no adverse effects. Also maximal recommended daily
dose should not be exceeded. Non-drug treatment (Box 9) should always be
combined with pharmacologic treatment of RLS of any severity. Because of high
prevalence of augmentation levodopa treatment should be avoided for long-term
treatment of RLS. Currently there is a trend among RLS specialists to start treat-
ment with alpha-2-delta ligands as the first line therapy because of occurrence of
augmentation even with DA treatment.
Step 2. The next step which is most important is to make the diagnosis of
augmentation based on the criteria as discussed above (see Box 5).
Step 3. Review the list of medications including OTC drugs.
Step 4. Eliminate or minimize those drugs and agents known to aggravate RLS
(e.g., antidepressants including SSRIs and SSNRIs, antipsychotics, antiemetics, and
antihistamines found in most of the OTC sedative-hypnotics.
Step 5. Review iron status (e.g., serum iron, ferritin which should not be below
50–70 ng/ml, and transferrin saturation, and treat if needed with oral ferrous sul-
phate and ascorbic acid facilitating its absorption.
Step 6. Address other factors predisposing to augmentation (see Box 6).
Step 7. For mild augmentation: Split the dose of DA between evening and
afternoon or add an extra dose of DA in the afternoon.
Step 8. For moderate to severe augmentation:
266 S. Chokroverty
• Reduce the dose or gradually taper off DA (e.g., reduce pramipexole by 0.25 mg
every 3–4 days; reduce ropinirole by 0.5 mg every 3–4 days).
• RLS symptoms will be severe initially but improvement will begin to occur in
5–6 days and significantly after about 10 days. During the withdrawal period of
DA, however, some patients may suffer from extremely severe RLS symptoms
with severe sleep disturbance.
• Continue non-drug therapy (see Box 9) during the withdrawal period.
Step 9. An alternative option is to follow this step (personal preference).
• Substitute DA drug partly with a different class of medication (e.g., gabapentin,
pregabalin or gabapentin enacarbil) along with gradual tapering of DA (for some
period patients will be on both medications.
Step 10. In some cases, substituting with a sustained release DA (e.g., rotigotia
patch) with or without an additional drug from a different class (e.g., alpha-2-delta
ligands) may help.
Step 11. If these measures fail to relieve the symptoms, use opioids (generally
medium to high potency agents [e.g., oxycodone, hydrocodone, methadone; see
Box 2] are needed but may try low potency drugs [e.g., codeine, propoxyphene,
tramadol] initially).
Step 12. Polypharmacy (two, three or even four drugs [e.g., opioids, DA,
alpha-2-delta ligands, oral iron] in divided doses) may be needed for relief of symp-
toms. With polypharmacy it may be possible to minimize doses and side effects.
Step13. Must watch for opioid side effects (e.g., severe constipation, sleep
apnea, tolerance, dependence, addiction, overdose, drug diversion, and
opioid-induced hyperalgesia [see further on]).
Step 14. Intravenous iron (if iron stores are low).
Step 15. If the above measures fail:
• Buprenorphine (sublingual) or
• Fentanyl patch
Step 16. If all measures fail:
• Intrathecal or Epidural morphine (Vahidi et al. 1994; Hornyak and Kaube 2012;
Lidvall et al. 2013; Jakobsson and Ruuth 2002),
• Deep brain stimulation (DBS) [see further on].
There are no guidelines or recommendations for these measures which remain
currently inconclusive.
Step 17. Finally, the role of “Drug Rotation” or “Drug Holidays” to prevent
“refractoriness” and “augmentation” remains unknown.
A note of caution is warranted for “Drug Holidays” or abrupt withdrawal of DA
medication because this may lead to neurologic malignant syndrome-like reaction,
although such an outcome has not been reported so far in RLS.
2. “Sleep Attacks” and Excessive Sleepiness

The impact of RLS on sleep and sleep architecture has been described above and in
this section the question of “sleep attacks” and excessive daytime sleepiness
(EDS) after DA therapy will be briefly discussed. Since Frucht et al. (1999) reported
sleep attacks or sudden onset of sleep (SOS) and EDS in Parkinson’s disease
(PD) patients on DA treatment, clinicians and particularly movement disorder spe-
cialists have been sensitized to the problem of SOS and EDS in patients with PD and
RLS on Da therapy. It was subsequently thought that SOS and EDS may have resulted
from a combination of medications and the disease itself. Most patients had SOS on a
background of increased sleepiness. In contrast, most RLs patients are hyperalert
despite nocturnal sleep disruption (see previous section), although a small subgroup of
RLS patients complain of EDS. In a questionnaire survey of 156 RLS patients and 126
healthy controls Moller et al. (2006) found a slightly higher prevalence of SOS in RLS
patients than in controls, but there was no significant difference between the groups in
their ESS sores. There was no association between SOS and duration or severity of the
disease. An important observation in this study is an increased risk of motor vehicle
accidents in those RLS patients complaining of SOS compared with those not com-
plaining of SOS. In contrast to PD patients, treatment with DA reduced the risk of SOS
in RLS. There is a report (Bassetti et al. 2002) of apparent “Sleep Attacks” in a single
RLS patient during withdrawn from pergolide (an erogoline-based DA). It should be
noted that dopaminergic agents have a biphasic action: Sedating with low dose but
activating at higher dose (Bassetti et al. 2002). The question of SOS and EDS in RLS
remains controversial and further studies are needed.
3. Peripheral edema and Weigh gain
An occasional side effect of DA mediation is peripheral leg edema contributing
to weight gain, although this is more common with alpha-2-delta ligands than with
DA. Associated chronic sleep disruption, compulsive eating behaviors and
depression may be cited as other factors for weight gain in RLS.
4. Site Reaction
This side effect applies only to rotigotine patch treatment. A site reaction is noted
in 10–25 % of patients depending on the size of the patch and adherence to
instructions regarding application of the patch; the overall frequency is about 17 %.
5. Fibrotic Complications
These complications have been noted only with ergoline DA medications (e.g.,
pergolide, cabergoline) and include fibrotic cardiomyopathy, pleuropulmonary and
retroperiotoneal fibrosis. Because of these potentially dreaded complications, these
drugs are currently not recommended for RLs treatment.
6. Impulse Control Disorders
Impulse control disorders (ICDs) encompass impulsive and compulsive behavior
characterized by a “failure to resist an impulse drive or temptation to perform an act
268 S. Chokroverty
that is harmful to the person or to others” (Evans et al. 2009). These have originally
been reported in certain percentage of PD patients on dopaminergic medications
(Evans et al. 2009). These behaviors were thought to be rare in RLS patients on
long-term DA treatment but several recent reports suggested their occurrence in
large number of RLS patients (7–17 %) (Earley and Silber 2010; Quckfall and
Suchowersky 2007; Tippmann-Peikert et al. 2007; Driver-Dunckley et al. 2007;
Provini et al. 2008; Cornelius et al. 2010; Ondo and Lai 2008; Pourcher et al. 2010;
Mestre et al. 2013; Dang et al. 2011; Voon et al. 2011; Bayard et al. 2013; Moore
et al. 2014; Abler et al. 2009). It has been suggested that these
impulsive-compulsive behaviors result from complex disinhibitory psychomotor
dysfunction related to an aberrant or excessive dopamine receptor stimulation
resulting in repetitive and reward-seeking behavior (Evans et al. 2009). The reward
and pleasure seeking brain circuits in the mesolimbic dopamine pathway (Fig. 1)
involving ventral tegmental area (VTA) with its connecting nucleus accumbens
(NA) (along with inputs from ventral striatum and connections to
orbitofrontal/ventromedial prefrontal cortex) are regulated by dopamine with
specific stimulation by dopamine D3 receptors (and concomitant down regulation
of (Evans et al. 2009) D2 receptors) (Mestre et al. 2013), Dopaminergic medica-
tions by inducing dopamine surges in the limbic system are believe to participate in
drug reward and natural motivational phenomena, such as food and sex (Evans
et al. 2009; Baler and Volko 2006). Some RLS patients on DA therapy may be
subjected to an excessive dopamine receptor stimulation of the limbic VTA-NA
regions causing a variety of ICDs (Box 10): compulsive gambling, shopping
nocturnal or binge eating, smoking, punding, compulsive medication use, and
hypersexuality (Earley and Silber 2010; Quckfall and Suchowersky 2007;
Tippmann-Peikert et al. 2007; Driver-Dunckley et al. 2007; Provini et al. 2008;
Cornelius et al. 2010; Ondo and Lai 2008; Pourcher et al. 2010; Mestre et al. 2013;
Dang et al. 2011; Voon et al. 2011; Bayard et al. 2013; Moore et al. 2014).
Fig. 1 Schematic diagram

showing mesolimbic
dopamine reward seeking
brain circuits involved in
impulse control disorders.
PFC Prefrontal cortex; VTA
Ventral tegmental area; NA PFC
Nucleus accumbens;
A Amygdala; HC VTA
Hippocampal commissure;
NA
Upper arrow Input from HC
anterior cingulate area; Lower A
arrow Input from Amygdala.
Reproduced with permission
from Moller et al. (2006) in
the text
A functional magnetic resonance (fMRI) of the brain in 12 RLS patients showed

ventral striatal activation when performing a gambling game task only when on
dopaminergic medication (Abler et al. 2009). The impulsive-compulsive behaviors
have been observed more in PD (25 %) than in RLS (9 %) patients. This finding is
possibly related to higher dose of medication ingested by PD patients but ICDs
have been noted in RLS patients on very low doses (Earley and Silber 2010).
Dopamine dysregulation syndrome (Leu-Semenescu et al. 2009) in one and drug
hoarding (Salas et al. 2009) in another RLS patient may also be cited as examples of
ICDs. At every follow-up visit of RLS patients on DA treatment physicians should
enquire about these impulsive-compulsive behaviors and patients should be warned
about the occurrence of ICDs while on DA treatment. The predictors for ICDs in
PD have been suggested in some reports (Mestre et al. 2013) but no studies have
clearly defined the predictors of ICDs in RLS (Ondo and Lai 2008); however, it is
known that a reduction of DA dose will improve the behavior. In some patients, DA
has to be stopped completely and alternative therapies such as opioids or an
alpha-2-delta ligands (gabapentin, pregabalin, or gabapentin enacarbil) need to be
considered for relief of RLS symptoms. During discontinuation of DA therapy
patients should be monitored closely for possible DA withdrawal syndrome
(Rabinak and Nirenberg 2010) or neuroleptic malignant-like syndrome, however,
such a syndrome has not been reported in RLS. For treatment of ICDs, some
authors proposed DBS which is though to improve ICDs because of discontinuation
of DAs (Ardouin et al. 2006). However, ICDs, including DDS and punding
worsened and persisted in reports of surgical case series (Lim et al. 2009). Some
reports documented appearance of pathological gambling and DDS after DBS
(Smedling et al. 2007; Moum et al. 2012). Currently general consensus is that DBS
has no role in treatment of DA induced ICDs.
II. Long-Term Consequences Related to Opioid Ingestion (see Box 4)
i. Some General Comments

Before considering log-term treatment with opioids it is advisable to pay
attention to current controversy and warning about the danger of long-term use of
opioids. There is a startling statistic that shows that in the last 15 years the pre-
scription for opioids for non-cancerous pain has quadrupled in the USA. We are in
the midst of a national opioid epidemic (Frieden and Houry 2016; CDC guideline
for prescribing opioids for chronic pain—United States 2016; Volkow and
McLellan 2016). Concomitantly, incidence of dependence, addiction, overuse and
deaths rose dramatically, and in fact opioid-related deaths have exceeded those due
to motor vehicle crashes (CDC guideline for prescribing opioids for chronic pain—
United States 2016; Volkow and McLellan 2016). Because of increasing danger
due to long-term use of prescription opioids the Food and Drug Administration
(FDA) is cautioning physicians and the centers for Disease Control (CDC) released
a “Guideline for Prescribing Opioids for chronic pain” (CDC guideline for
270 S. Chokroverty
prescribing opioids for chronic pain—United States 2016). Physicians should first
carefully consider whether the benefits outweigh the dangers, and discuss with the
patients the pros and cons before prescribing opioids for long-term use. Next the
most important principle is to “Start low and go slow” (Frieden and Houry 2016).
Third, the prescriber should evaluate medication history including history of drug
abuse because such history should signal not to use opioids if at all possible. Also
physicians should monitor patients closely including urinary drug screening before
and periodically during treatment, and watch for adverse effects which are described
below.
ii. Tolerance
(See also under “Long-term consequences of DA Treatment”). In a large per-
centage of patients the efficacy of medicine wears off requiring increasing dose
because of down regulation of opiate mu receptors (Frieden and Houry 2016; CDC
guideline for prescribing opioids for chronic pain—United States 2016). This may
depend on individual demographic characteristics and other factors not definitely
known at present.
iii. Dependence
This could be both physical and psychological, and is not an uncommon com-
plication of long-term opiate use. The prevalence of opioid dependence has been
reported to be as high as 26 % among primary care patients on opioid for
non-cancer-related pain (Frieden and Houry 2016; CDC guideline for prescribing
opioids for chronic pain—United States 2016). This generally disappears in course
of days to weeks after discontinuation of medication.
iv. Addiction
Addiction to opioids is a serious clinical and social problem. As a result of
widespread use of opioids there is an epidemic of opioid addiction and deaths from
overdose (Volkow and McLellan 2016). Addiction is noted in 2–6 % of patients on
long-term opioids. In contrast to dependence addiction is less common but more
difficult to treat. The craving for medication persists much longer than dependence
(e.g., weeks to months vs. days to weeks) after discontinuation of medicine. These
two adverse effects, dependence and addiction utilize different mechanisms for their
occurrence. The molecular mechanism of addiction evolves slowly and lasts longer
involving multiple brain regions. There is a tendency to overuse leading to overdose
and deaths in many patients.
v. Opioid Use Disorder (OUD)
This is highly prevalent among long-term opioid user and is a serious psychiatric
illness resulting in antisocial behavior, socioeconomic hardship, physical and
sexual abuse, depression, and even deaths in may patients (American Psychiatric
Association 2013). The American Psychiatric Association listed diagnostic criteria
for OUD (American Psychiatric Association 2013). At least two of the 11 criteria
within a 12-month period must be satisfied for diagnosing OUD. Some examples of
these criteria include the following: craving for opioids, recurrent use despite
problems at work or home and with social or interpersonal relationships, use of
medication under physically hazardous conditions, tolerance, characteristic opioids
withdrawal syndrome, etc. To relieve or avoid withdrawal symptoms patient takes
the same opioid or substance closely related to this. The evaluation of patients with
OUD should follow the suggestions outlined in the beginning of this section (II.i)
under general comments. A detailed discussion about treatment of opioid-related
dependence, addiction, and OUD is beyond the scope of this chapter; however,
treatment of patients with buprenorphine (a partial opioid agonist), methadone (a
full opioid agonist), or naltrexone (an opioid antagonist) has been shown to improve
outcomes (Frieden and Houry 2016).
vi. Drug Diversion
This simply means transfer of a legitimately prescribed substance from an
individual for whom it was prescribed to someone else for illicit use. Drug diversion
is on the rise among drug abusers, particularly among long-term opioid users
suffering from dependence, addiction, and OUD. Drug diversion is a growing risk
to safety of the patients, their friends, and families to whom the drug is illegally
diverted. Stealing the drug, doctor shopping, claiming not to have received pre-
scription in the mail are some of the measures used in getting the medication,
hoarding them, and later transferring to family members or friends. Drug diversion
also is a problem within health care facilities. There are rules, regulations and
preventive measures available to tackle this growing problem (CDC guideline for
prescribing opioids for chronic pain—United States 2016; Berger et al. 2012).
vii. Sleep Apnea
The true prevalence of sleep apnea in RLS is not known. Limited clinical and
polysomnographic studies raised the question of increasing prevalence of
obstructive sleep apnea (OSA) in RLS (Bianchi et al. 2016; Chokroverty and
Sachdo 1984; Schonbrunn et al. 1990). One study (Delgado et al. 2006) showed
that following treatment of OSA by continuous positive airway pressure (CPAP)
titration patients with comorbid RLS and OSA showed improvement in both RLS
symptoms and OSA related symptoms. These findings remain controversial until
confirmed in a large number of patients in future studies Physicians treating RLS
patients with opioids or clonazepam should monitor these patients closely and pay
particular attention to possible adverse effects of opioids and clonazepam on
breathing. Opioids have a direct depressing effect on brain-stem respiratory neurons
and can cause central apnea including ataxic breathing (Fig. 2) or Cheyne-Stokes
breathing (Fig. 3). Patients on long-term opioids should be monitored periodically
by clinical evaluation and polysomnographic study to diagnose sleep apnea
(Walters et al. 2001). It is best not to use opioids and clonazepam both together in
the same patient to minimize their side effects.
272
Fig. 2 A 180-s excerpt taken from bilevel titration study in a 39 year-old man on large doses of opioids (oxycodone, morphine sulfate and
hydromorphone) for chronic severe low back pain and BiPAP for sleep apnea (mixed obstructive and central) is shown. This epoch shows episodes of
ataxic breathing (periodicbreathing with irregular pauses of respiratory effort and flow channels). Top eight channels: Electroencephalogram
(EEG) [International electrode placement; referential montage with connection to contralateral mastoid]; M2 Right mastoid; M1 Left mastoid; E1-M1
Left eye referenced to left mastoid; E2-M1 Right eye referenced to Left mastoid; Chin 1–Chin 3 Electromyogram (EMG) of the mentalis muscle; EKG
S. Chokroverty
Electrocardiogram; HR Heart rate; LTIB and RTIB Left and right tibialis anterior EMG; LGAST and R GAST Left and right gastrocnemius EMG;
CFlow BiPAP flow channel; ABD and Chest Respiratory effort channels from abdomen and chest; SaO2 Arterial oxygen saturation by finger oximetry
viii. Opiod Induced Hyperalgesia

Opioid induced hyperalgesia (OIH), observed in some patients on long-term
opioids for pain (both cancer-related and non-cancer pain), resembles opioid tol-
erance which is defined as decreased efficacy in course of time requiring dose
escalation with improvement of pain (Frieden and Houry 2016; Volkow and
McLellan 2016; Mao 2010; Lee et al. 2013; Stoica et al. 2015; Amgst and Clark
2006; Chu et al. 2008). In contrast, to tolerance, however, dose increase in OIH
causes increased pain sensation. OIH therefore can be defined as a paradoxical state
of increased pain sensation after continued use of opioids. OIH has been observed
in both animal and human studies (Mao 2010; Lee et al. 2013; Stoica et al. 2015;
Chu et al. 2008). In OIH there may be allodynia (i.e., perceived pain caused by
stimuli that normally do not cause pain) which is not seen in opioid tolerance.
Clinical clues for OIH can be summarized as follows: increasing intensity of pain
above the baseline on increasing the dose of opioids (paradoxical response);
worsening of persistent pain; changing characteristic of pain from those of the
original pain, e.g., pain arising in different locations, becoming more diffuse and
spreading beyond the original locations; and in some cases development of allo-
dynia. Thus OIH resembles symptoms of dopamine induced augmentation (DIA),
but they are mediated by two different mechanisms. Suggested mechanisms for OIH
include the following: central pain sensitization as a result of activation of n-
methyl-d-acetate (NMDA) receptors leading to glutamatergic excitation coupled
with descending facilitation of pronociceptive pathways from rostral ventromedial
medulla due to neuroplastic changes triggering the release of spinal cord dynorphin;
and probably also immune cell expressed inflammatory spinal cytokines (e.g.,
interleukin 1B) causing sensitization of primary afferent (peripheral) and second
order neurons.
OIH has been reported in a case of intractable and refractory RLS (Chokroverty
2015a, b; Vertrugno 2015). Two previous reports (Earley and Allen 2006; Vetrugno
et al. 2007) of DIA-like features in RLS patients on long-term tramadol (a synthetic
opioid [codeine derivative] actually fulfill the criteria for OIH. It is noteworthy that
rare cases of RLS-like symptoms (both transient and persistent) have been
described in opioid-dependent subjects during opioid withdrawal (Ghosh and Basu
2014), which may cause a dopamine-and-opioid depleted state. Although symp-
toms of DIA and OIH are somewhat similar, but as stated above these two entities
are based on two different mechanisms (predominantly cellular in OIH and neu-
rotransmitter or neuromodulator in DIA) (Mao 2010; Amgst and Clark 2006; Chu
et al. 2008).
Treatment Options for OIH
These are just suggested steps and there are no standard guidelines: (Frieden and
Houry 2016; Volkow and McLellan 2016; Chu et al. 2008)
Step 1. Dose escalation initially to differentiate OIH from opioid tolerance
(Sometimes it is a challenge and is very difficult to distinguish these two entities); if
pain improves, it suggests tolerance, but if pain worsen, it favors OIH.
274
Fig. 3 A 300-s excerpt showing crescendo-decrescendo pattern of classic Cheyne-Stokes (CSB) breathing from an overnight polysomnographic study during
stage N2 of a 72-year-old man with a history of heart failure. The CSB was present during most of the non-rapid eye movement (NREM) sleep with marked
decrease or absence during REM sleep. Note longer duration of hyperventilatory than apneic phase and prolonged circulation time (measured form the
termination of apnea to the lowest oxygen saturation noted in the middle of next apneic phase. Top four channels: EEG (international nomenclature with
electrods referenced to contralateral ears [A2 right ear; A1 left ear]); LOC and ROC left and right oculograms; Chin mentalis EMG; EKG Electrocardiogram;
S. Chokroverty
LT and RT TIB left and right tibialis anterior EMG; ORONAS Airflow (thermistor); THORAX and ABDM Respiratory effort channels; SaO2 Arterial oxygen
saturation by finger oximetry
Step 2. Initiate opioid tapering by gradually reducing the opioid dose.

Step 3. Use adjuvant therapies during taper:
• NMDA receptor antagonists (e.g., dextromethorphan, ketamine)
• Non-steroidal antinflammatory drugs (NSAIDs) or Cox-2 inhibitors
• Alpha-2 receptor agonist (e.g., clonidine)
• Tricycidia antidepressants, SSRIs, or SSNRIs,
• Gabapentin, a GABA analog (inhibits alpha-2-delta voltage-gated calcium
channel [VGCC] ligands)
• Memantin (a derivative of amantadine and prevents excessive receptor
activation)
Step 4. (Alternative to Steps 2 and 3)
1. Opioid rotation by switching to a different opioid
C. Deep Brain Stimulation

Deep brain stimulation (DBS) targeting either globuspallidus internus (GPI) or
subthalamic nucleus (STN) has a clear role in selected patients with PD but the
potential role of DBS in treating RLS patients is undetermined at present. There
are isolated reports with contradictory results (Driver-Dunckley et al. 2006;
Ondo 2006; Kedia et al. 2004; Marques et al. 2015). In RLS there is no loss of
nerve cells in the basal ganglia, which may call into question the rationale for
use of DBS in RLS.
5 Conclusion
It is essential to comprehend long-term consequences of RLS/WED including

natural history of the illness (e.g., is it a chronic progressive disease or an entity
with intermittent symptoms, and eventual remission in a number of cases?), and
management problems of RLS patients on long-term dopaminergic drugs or opi-
oids. This knowledge is important for an understanding of biology of the disease
and for designing satisfactory treatment. This chapter summarized some of the
known facts and brought out many controversies surrounding this entity in search
of an identity. Despite rapid progress in multiple directions in our understanding of
the disease, we remain ignorant about fundamental pathophysiology of RLS.
Briefly, RLS appears to be a widespread systemic biochemical disorder associated
with brain iron deficiency and hypoxic pathway activation without any structural
alteration. These abnormalities result in changes in brain circuits including resting
state connectivity manifested by brain dopamine dysregulation, decreased myeli-
nation and white matter, increased cortical excitability, and disordered
somatosensory processing. Thus RLS can be considered a disorder of brain circuits.
276 S. Chokroverty
RLS is probably the commonest movement disorder which is often

under-diagnosed or misdiagnosed. Physicians treating this condition with
dopaminergic medications or opioids should be aware of long-term management
problems and be ready to diagnose, treat, and prevent long-term adverse
consequences.
BOX 1. Essential Diagnostic Criteria for RLS/WED
1. An urge to move the legs, usually accompanied by uncomfortable leg sensations
(but not always);
2. Beginning or worsening of symptoms during quiescence, such as lying or
sitting;
3. Partly or totally relieved of symptoms by movement, such as walking or
stretching, at least as long as the activity continues;
4. Symptoms are exclusively present in the evening or at night, or worse than
during the day, at least in the early stage;
5. These symptoms are not solely explained by another medical or behavioral
condition (so-called RLS mimics).
BOX 2. Pharmacologic Agents Commonly used to treat RLS/WED
• Alpha-2-delta Calcium Channel Ligands
– Gabapentin Enacarbil (FDA Approved)
– Pregabalin
– Gabapentin
• Depamine Agonists
– Pramipexole (approved)
– Ropinirole (approved)
– Rotigotine Patch (approved)
• Opioids
– Oxycodone
– Hydrocodone
– Hydromorphone
– Methadone
– Buprenorphine
– Oxycodone/naloxone (approved in Europe)
– Codeine
– Propoxyphene
• Benzodiazepines
– Clonazepam
– Lorazepam
• Iron Therapy
– Oral iron with ascorbic acid (for those with low serum iron or ferritin level
below 50–70 ng/ml)
– Intravenous iron (those not responding to oral iron and showing iron
deficiency)
BOX 3. Disease-Related Issues
1. Impact of RLS on sleep and its consequences
2. Burden and course of the disease-impaired health and quality of life
3. Acute exacerbartion and “break through” RLS Symptoms
4. Depression and Anxiety (“AnxietasTibiarum”)
5. Cardiovascular and cerebrovascular consequences
6. Obstructive Sleep Apnea and RLS
BOX 4. Medication-Related Issues
A. Long-term consequences related to dopaminergic medication
• Augmentation, an iatrogenic side effect
• Rebound
• Tolerance
• Sleepiness and “sleep attacks”
• Impulse Control Disorders (ICDs)
• Fibrotic Complications
• Peripheral edema and weight gain
• Site reaction
B. Long-term consequences related to opioid ingestion
• Tolerance
• Dependence (Physical and Psychological)
• Addiction
• Opioid use Disorder (OUD)
• Drug Diversion
• Opiod-Induced Hyperalgesia (OIH)
• Sleep Apnea
BOX 5. Diagnostic Criteria for Augmentation
A. Prior response to dopaminergic medication
B. An increase of symptom severity 5/7 days for which no other cause is apparent
278 S. Chokroverty
C. A Paradoxical response to medication

D. An earlier onset of symptoms by at least four hours
OR
• An earlier onset between 2 and 4 h
PLUS
• One of the following:
– Shorter latency to symptoms when at rest
– Extension of symptoms to other body parts
– Greater intensity of symptoms compared with prior symptoms
– Decreased duration of medication benefit
Augmentation ¼ A þ B þ C;
¼ A þ B þ D;
¼ AþBþCþD
BOX 6. Factors for Augmentation

• Larger dose of the medication
• Longer duration of treatment
• Severity of the disease
• Half-life of the medication
• Low serum ferritin (iron deficiency)
• Chronic sleep deprivation
• Comorbid conditions
• Individual characteristics
• Effect of heredity
BOX 7. Suggested (hypathetical) Mechanisms for Augmentation
• An imbalance between dopamine (excess) and acetylcholine (relative defi-
ciency) in the basal ganglia.
• Excessive hypocretinergic (orexinergic) stimulation causing hypermotor syn-
drome via direct projections to brain stem and spinal motor neurons, and
indirectly via projections to monoaminergic systems.
• Domaminegic system hyperactivation at higher dose.
• Excessive stimulation (excitotoxicity) of dopamine receptors may desensitize
the receptors (receptor downregulation) through a stage of tolerance.
• A combination of loss of presynaptic dopamine storage capacity and postsy-
naptic receptor alteration similar to suggested mechanism for motor fluctuation
in Parkinson’s disease.
• Dopamine receptor supersensitivity similar to mechanism suggested for levo-
dopa and tardive dyskinesia.
BOX 8. Suggested (hypothetical) sites or pathways utilized in Augmentation

• Ventral Tegmental Area (VTA) and Nucleus Accumbens (Mesolimbic System):
Possible site but not proven
• Diencephalo-Spinal Pathway: Probable site but not proven
• Both presynaptic and postsynaptic dopamine receptor pathways: not proven.
Box 9. Non-Pharmacologic Treatment of RLS
• General Sleep hygiene measure
• (e.g., regular bedtime and wake-up time; avoid alcohol and smoking in the
evening; avoid caffeinated beverages after early afternoon; attend to bedroom
environment conducive to sleep; avoid spicy and heavy meals at dinnertime;
avoid planning next day’s activities at bedtime)
• Eliminate or reduce medications that may worsen RLS
• Participate in moderate exercise regularly (avoid vigorous exercise which may
aggravate RLS symptoms).
• Participate in mentally alerting activities including distraction from symptoms
which may benefit RLS symptoms.
• Take part in counter stimulation measures; e.g., getting up and walking, mas-
saging the legs, hot or cold showers.
Box 10. List of Impulse Control Disorders Reported in RLS/WED patients
taking Dopamine Agonist
• Pathological gambling
• Compulsive shopping
• Compulsive smoking
• Hypersexuality
• Nocturnal Eating
• Punding
• DopamineDysregulation Syndrome
• Drug Hoarding
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Dopamine and Sleep

ISBN 978-3-319-46435-0 ISBN 978-3-319-46437-4 (eBook)

© Springer International Publishing Switzerland 2016

Printed on acid-free paper

This Springer imprint is published by Springer Nature

regimens may be modiﬁed as new clinical research accumulates, readers are

Montevideo, Uruguay Jaime M. Monti

Dopamine in REM Sleep Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Depression, Sleep Disorders, and DA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

Darío Acuña-Castroviejo Institute of Biotechnology, Biomedical Research

Mudasir Ahmad Khanday School of Life Sciences, Jawaharlal Nehru University,

Todd J. Swick University of Texas School of Medicine-Houston, Houston, TX,

Mudasir Ahmad Khanday, Raghunandan Kumar Yadav

M.A. Khanday R.K. Yadav B.N. Mallick (&)

© Springer International Publishing Switzerland 2016 1

RBD REMS behavior disorder

1 Sleep and REMS

Sleep is an instinct, naturally occurring, recurrent and reversible physiological

2 Neural Regulation of REMS

Based on experimental lesion, transection, single neuronal activity recording and

Based on such criteria a group of noradrenaline (NA)-ergic neurons in locus

3 Withdrawal of Inhibition Induces REMS

5 Location of DA-ergic Neurons

Dahlstrom and Fuxe (1964) described distribution of catecholaminergic neurons in

Based on the differences in drug speciﬁcities and signaling mechanisms initially

7 Intrinsic Regulation of Firing of DA-ergic Neurons—

Several studies showed the presence of autoregulatory mechanism for release of

activation of D2 receptors. Intra-nigral delivery of amphetamine (DA-agonist)

PD is a neurological disorder that affects motor coordination as a result of

10 DA and REMS Behavior Disorder

REMS behavior disorder (RBD) is characterized by vigorous muscle activity and

11 Involvement of DA-D1 Receptors in Sleep

12 DA-ergic System and REMS Regulation

Fig. 1 DA-ergic modulation of REMS in health and diseases: a model

Aghajanian GK, Bunney BS (1977) Dopamine “autoreceptors”: pharmacological characterization

Bjorklund A, Lindvall O (1975) Dopamine in dendrites of substantia nigra neurons: suggestions

Ehringer H, Hornykiewicz O (1960) Verteilung von Noradrenalin und Dopamin

Hublin C, Launes J, Nikkinen P, Partinen M (1994) Dopamine D2-receptors in human narcolepsy:

MacFarlane J, List S, Moldofsky H, Firnau G, Chen J, Szechtman H, Garnett S, Nahmias C (1997)

Schenck CH, Mahowald MW (1990) A polysomnographic, neurologic, psychiatric and clinical

Abstract Pharmacological agents which increase dopaminergic neurotransmission

The dopaminergic neurotransmitter system is one of the most intensely investigated

R.E. Brown (&)

© Springer International Publishing Switzerland 2016 19

1 History of Dopaminergic Stimulants

2 Psychostimulants Promote Dopaminergic

adrenaline) is tyrosine hydroxylase (TyH), which converts L-tyrosine to L-DOPA.

3 Location of Dopaminergic Cell Groups Controlling

The potent wake-promoting action of cocaine, amphetamines and modaﬁnil and

4 Midbrain Dopamine Neurons Increase Arousal

Large, non-speciﬁc, electrolytic lesions of midbrain dopamine neurons and sur-

Very recently, in vivo calcium imaging from VTA dopaminergic neurons

5 Brainstem Dopaminergic Neurons Have Increased

In contrast to VTA and SN dopamine neurons, dopaminergic neurons in the ventral

6 Effector Mechanisms of Dopaminergic Control

Neurotransmitters and neuromodulators exert their effects on their targets by

7 Dopaminergic Control of Arousal in Drosophila

Dopaminergic neurotransmission not only regulates arousal in vertebrates but even

8 Effect of Sleep Deprivation on Dopaminergic