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Neuropharmacological basis of vestibular

system disorder treatment
ARTICLE in JOURNAL OF VESTIBULAR RESEARCH JANUARY 2013
Impact Factor: 1.46 DOI: 10.3233/VES-130494 Source: PubMed
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Enrique Soto
Rosario Vega
Meritorious Autonomous University of Puebla
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119
Journal of Vestibular Research 23 (2013) 119137

DOI 10.3233/VES-130494
IOS Press
Neuropharmacological basis of vestibular

system disorder treatment
Enrique Soto , Rosario Vega and Emmanuel Sesea
Instituto de Fisiologa, Universidad Autnoma de Puebla, Puebla, Mxico
Received 23 November 2012

Accepted 7 May 2013
Abstract. This work reviews the neuropharmacology of the vestibular system, with an emphasis on the mechanism of action of
drugs used in the treatment of vestibular disorders. Clinicians are confronted with a rapidly changing field in which advances in
the knowledge of ionic channel function and synaptic transmission mechanisms have led to the development of new scientific
models for the understanding of vestibular dysfunction and its management. In particular, there have been recent advances in
our knowledge of the fundamental mechanisms of vestibular system function and of drug action. In this work, drugs acting
on vestibular system have been grouped into two main categories according to their primary mechanisms of action: those with
effects on neurotransmitters and neuromodulators dynamics and those that act on voltage-gated ion channels. Particular attention
is given in this review to drugs that may provide additional insight into the pathophysiology of vestibular diseases. The critical
analysis of the literature reveals that there is a significant lack of information defining the real utility of diverse drugs used in
clinical practice. The development of basic studies addressing drug actions at the molecular, cellular and systems level, combined
with reliable and well controlled clinical trials, would provide the scientific basis for new strategies for the treatment of vestibular
disorders.
Keywords: Inner ear, vertigo, dizziness, Mnires disease, vestibular nuclei, hair cells, excitatory amino acids, antihistaminic,
neuropeptides, ionic channels
1. Introduction
In the vestibular endorgans, drugs that act on the
vestibular apparatus have diverse cellular targets including the homeostasis of liquids and electrolytes in
the inner ear, regulation of blood flow, cell homeostasis
and survival, and sensory processes related to vestibular information flow (Fig. 1). In the vestibular nuclei
drug actions are related to homeostasis and cell survival, and to neurotransmitter receptors and ion channels modulation (Fig. 2). In this work we concentrate our attention in those drugs with direct effect on
the neuronal dynamics of vestibular endorgan and of
vestibular nuclei. Drugs acting on vestibular system
Corresponding author: Enrique Soto, Instituto de Fisiologa,
BUAP, 14 sur 6301, CU, San Manuel, Puebla, Pue., CP 72570, Mxico. Tel.: +52 222 2295500 ext 7316; E-mail: esoto24@gmail.com.
have been grouped into two main categories according to their primary mechanism of action: those with
effects on neurotransmitters and neuromodulators dynamics and those that act on voltage-gated ion channels.
From a pharmacological point of view, it is necessary to emphasize that the central portion of the
vestibular system is relatively isolated from the systemic blood flow by the blood-brain barrier, whereas
the periphery of the vestibule is also isolated by the
blood-labyrinth barrier. Because of this, some drugs
can affect one region without affecting the other. Also
the differential expression of neurotransmitter receptor subclass and ionic channel types may contribute to
differentiate the central from the peripheral action of
drugs. Thanks to this, selective effects can be afforded.
Strategies have also been designed to allow the local
administration of some drugs, thus limiting their systemic effects.
c 2013 IOS Press and the authors. All rights reserved

ISSN 0957-4271/13/$27.50
120
E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment
Fig. 1. Pharmacological targets at the vestibular periphery. Scheme shows the series of processes leading to sensory coding in the vestibular
neuroepithelia, from mechanical stimuli to spike discharge. Several of these processes are the subject of modulation by drugs used in the treatment
of vestibular disorders. The ion channels blockers affect the hair cell response (decreasing the receptor potential and/or synaptic neurotransmitter
release), the efferent neurons activity (also modifying the neurotransmitter release), or directly act in the afferent neurons changing the neuron
excitability and its action potential discharge. The agonists and antagonists of various neurotransmitters modulate the efferent or the afferent
synaptic input either to the hair cell or to the afferent neuron. MET: mechanoelectrical transduction.
2. Drugs with effects on receptors for

neurotransmitters and neuromodulators
In the inner ear, hair cells of the vestibular neuroepithelium establish synapses with afferent neurons and
receive innervation from the efferent neuronal system. The main neurotransmitter of hair cell afferent
synapses is glutamate; efferent neuronal synapses release acetylcholine as the primary neurotransmitter.
Glutamate released at hair cell afferent synapses interacts with several subtypes of excitatory amino acid
(EAA) receptor, including N-methyl-D-aspartic acid
(NMDA), -amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA) receptors,
and metabotropic receptors [11,58,72,94,148,171,172].
The NMDA receptors participate in determining the
basal discharge and tonic response to sustained stimuli, whereas non-NMDA receptors seem to mediate responses to high-frequency mechanical stimulation [60,
72] (Fig. 3).
Hair cells and efferent neurons release diverse neuroactive substances, including calcitonin gene related
peptide (CGRP), substance-P, opioid peptides, endocannabinoids, -aminobutyric acid (GABA), ATP, nitric oxide, adenosine and histamine [58,72]. Apart
from the neurotransmitters that participate in the processing of sensory information, the vestibule also receives sympathetic and parasympathetic innervation, a
fact that probably accounts for the presence of catecholamines in the inner ear [67].
Vestibular system primary afferent neurons make
synapses with neurons of the vestibular nuclei, where
they release an EAA most probably glutamate and aspartate. Vestibular nuclei receive numerous and diverse
synaptic inputs that form part of the very complex integrative processes involved in postural control, gaze
stabilization, spatial orientation and navigation, and
modulation of the sympathetic nerve activity [142,152,
165].
The neurons of the vestibular nuclei express NMDA
and non-NMDA EAA receptors [38,69,192]. In addition, neurons of the vestibular nuclei express GABAA
and GABAB receptors and glycine receptors that show
an extensive colocalization with GABA receptors, his-
121
Fig. 2. Main pharmacological targets at the vestibular nuclei. Apart from the input from vestibular primary afferents, vestibular nuclei (VN)
receive a wide spectrum of afferent synapses from many regions of the brain, and also multiple intra and internuclear and commissural fibers,
constituting a complex neural network in which many neurotransmitter systems are involved as depicted in Figure 4. Drugs may affect various
processes including the input to the nuclei, the neuronal response, neuronal integration, excitability and action potential discharge. On the long
term other more complex effects involving network reorganization may also take place.
tamine H1 , H2 and H3 receptors [24], serotonine 5HT1

and 5HT2 receptors [75], adrenergic 2 receptors,
but also 1 and receptors [160], cholinergic muscarinic (mACh) and nicotinic (nACh) receptors in all
the vestibular nuclei [119], opioid receptors [182,183],
canabinoid CB1 receptors [168], neurotrophin Trk A,
B and C receptors (for a review, see [39] and glucocorticoid receptors (Fig. 4).
Most studies have addressed the study of medial
vestibular nucleus neurons, that are functionally dominated by tonic and phasic neurons [22]. These neurons
also have a cytochemical and pharmacological diversity that has been defined in various animal species.
A recent neuronal classification of the medial vestibular nucleus based in the genetic markers expression
has identified six major neuronal types, three inhibitory
(I1-3) that express Slc7a7 and/or Slc7a6, and three excitatory (E1-3), that express Gad1 and/or Gad2. The
sites of the projection of four neuronal types were: E1,
to motor nuclei of the contralateral eye; E2, to cerebellar mossy fiber neurons; I1 to the ipsilateral abducens
motor nucleus and; I3, to interneurons in the vestibular nucleus. Projections of E3 and I2 remain unidentified [100].
Vestibular nuclei neurons also produce neuroactive

compounds such as nitric oxide, which seems to play
a significant role in vestibular compensation [170]. Nitric oxide may account for some of the collateral effects of phosphodiesterase inhibitors, such as sildenafil, that can produce diplopia and dizziness in 2% of
patients. These secondary effects have been attributed
to the cardiovascular actions of these drugs, but it
seems likely that they could be caused by alterations
in vestibular activity, which, to our knowledge, has not
been studied in such patients. In fact, there are reports
of patients who develop severe vestibular symptoms
after a single 50 mg dose of sildenafil [76].
The complexity of the synaptic connections determining the activity of the afferent neurons in the
vestibular end organs, together with the intricate synaptology of the vestibular nuclei, determines that many
drugs acting on synaptic receptors may influence the
activity of the whole vestibular system network [55].
2.1. Excitatory amino acid related drugs
Diverse experimental models have demonstrated the
role of EAA receptors in excitotoxicity [44]. For this
122
Fig. 3. Scheme of the synaptic relationships of type I (right) and type II (left) hair cells. Type I hair cells are characterized by the large chaliceal
afferent innervation that covers its basolateral surface. Efferent fibers make synaptic contacts with the external surface of the calyx endings. In type
II hair cells, the afferent neurons form button type synapses, and the efferent neurons make synaptic contact directly upon the hair cell body. The
hair cell to afferent synapse uses glutamate as the principal neurotransmitter. At the postsynaptic cell glutamate interacts with several subtypes of
excitatory amino acid (EAA)-receptors including N-methyl-D-aspartic acid (NMDA), -amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid
(AMPA), kainic acid (KA) and metabotropic receptors. The efferent neurons are primarily cholinergic, and ACh released from afferent neurons
interacts with muscarinic (mACh) and nicotinic (nACh) receptors. The efferent neurons also release calcitonin gene related peptide (CGRP),
substance-P and enkephalins, which act on specific receptors (in the case of the opioid peptides opioid receptor in the hair cells and the
opioid receptors in the afferent neurons). Both the hair cells and the afferent neurons expressed the nitric oxide synthase (NOS) and may release
nitric oxide (NO). Hair cells also express H1 histamine receptors and the afferent neurons H3 and H4 histamine receptors. The hair cells typically
express purinergic receptors (ATP) in their apical portion.
reason, it has been proposed that EAA receptor antagonists, as well as calcium channel antagonists, may exert
a neuroprotective action in cases of ischemia or overactivation of EAA mediated synapses. In the cochlea
such over-activation may occur as a result of intense
sound exposure; in the case of the vestibule such a
mechanism has not yet been shown.
Trimetazidine (1-(2,3,4 trimethoxybenzyl) piperazine hydrochloride) is an anti-ischemic agent used in
cardiac disturbances and was also tested in the symptomatic treatment of vertigo. Trimetazidine inhibits excitotoxic damage produced by activation of EAA receptors [66], possibly by acting as a modulator of aerobic glycolysis. Antagonism of AMPA/KA receptors
of afferent neurons can also contribute to the beneficial
effects of trimetazidine [41]. In clinical tests, trimetazidine is as effective as betahistine in the treatment of
vertigo and dizziness [118]; multi-center studies have
confirmed the utility of trimetazidine in diverse disorders that produce balance alterations [5] and, although
discreet, in the reduction of the frequency and duration
of vertigo in Mnires disease patients [140]. Cautions
about the use of trimetazidine are because it can induce
parkinsonism, gait disorders, tremor, and at least one
case of coreiform manifestations related to its use has

been described [116,164].
Memantine (1-amino-3,5 dimethyiladamantane) is a
low-affinity noncompetitive NMDA receptor antagonist, although some reports indicate that it also acts
on serotonergic 5HT3 receptors, dopaminergic D2 receptors and cholinergic muscarinic and nicotinic receptors. Memantine has been used in the treatment of
various diseases. Numerous case reports have proven
the beneficial effect of memantine on acquired pendular nystagmus. Nevertheless, no controlled studies that
demonstrate its utility in the treatment of vestibular disorders have been published [179]. Somewhat similar
results have been reported for caroverine, a derivative
of quinoxaline that acts like a competitive antagonist of
the AMPA receptor; no controlled studies that support
its use in the clinical treatment of vestibular disorders
have been published.
Noncompetitive antagonists of the NMDA receptor, such as dizocilpine (dibenzo-cycle-penteno-imine,
also referred to as MK-801), phencyclidine and ketamine, have a significant use in basic research and
have been the subject of clinical trials. Dizocilpine
was used as a neuroprotective agent to prevent amino-
123
Fig. 4. Scheme depicts the complexity of synaptic input impinging in the vestibular nucleus neurons (VNN). It is necessary to consider that
the neurons of the nuclei are heterogeneous and not all the cells receive all types of synaptic influences. The main synaptic input to the VNN
is from the primary afferents, mediated by glutamate that interacts with NMDA, AMPA/KA and metabotropic receptors. Vestibular afferents
express a presynaptic metabotropic glutame receptor (mGluR). VNN also receive glutamatergic synapses originating from spinal cord neurons.
GABAergic fibers originating primarily from the cerebellum and from the contralateral vestibular nuclei impinge on the VNN, activating GABAA
and GABAB receptors. Histaminergic fibers originating from the tuberomammillar nucleus act on H1 , H2 and H3 receptors. Serotonergic fibers
from the raphe nuclei activate 5-HT1 and 5-HT2 receptors. These fibers also control the release of CGRP from vestibular nucleus neurons.
Intrinsic and commissural connections give rise to glycinergic fibers acting on inhibitory receptors. Noradrenergic fibers originating from the
locus coeruleus act primarily on 2 receptors, but also on 1 and receptors. Internuclear enkephalinergic fibers also make a synaptic input
to certain VNN acting on -opioid receptors, also the release of orphanin/nociceptin FQ acting on the opioid-like orphan receptor (ORL-1)
contribute to opioid input to VNN. The endocannabinergic type CB1 receptors have also been detected in the vestibular nuclei. The output of the
VNN is primarily by glutamatergic and cholinergic projections, but GABAergic and glycinergic projections have been demonstrated also. Finally,
the VNN express the NOS and may produce NO as a cellular messenger and also receive a modulatory input mediated by 17-beta-estradiol acting
on the E(2) receptors.
glycoside ototoxicity [21,57,77]. However, clinical trials showed no significant action of dizocilpine against
aminoglycoside ototoxicity [138]. Phencyclidine is a
noncompetitive NMDA receptor antagonist frequently
used as a recreational drug (PCP or angel dust); it has
important effects on vestibular activity. Specifically,
acute poisoning with phencyclidine induced intense
horizontal and vertical nystagmus [130]. Phencyclidine
has no known clinical use in vestibular pharmacology. Ketamine, a derivative of phencyclidine, is also an
NMDA receptor antagonist which is used in anesthesia
and antinociception. It has been reported to inhibit the
vestibular afferent neuron activity in frogs [212]. In patients with neuropatic pain, chronic administration of
ketamine always leads to dizziness as a major side effect [37]. Ketamine has been widely used as a recreational drug, it has been reported that it produced a significant alteration in perception of auditory, visual and
painful stimuli resulting in a general lack of responsive awareness. In some users nystagmus and a general incapability to move coordinately and orientate in
space, along with frequent falls is typical of ketamine
abuse [201].
Recently, neramexane which is an amino-alkylcyclohexane derivate that acts as a nicotinic receptor

channel blocker and noncompetitive NMDA receptor
antagonist, was found in double-blind randomized trials to have a modest efficacy in moderate to severe tinnitus [181].
2.2. Cholinergic drugs
Vestibular type II hair cells and vestibular afferent
neurons are innervated by efferent neurons (Fig. 3),
which exert central control of the vestibular responses
based on the movement programs of the subject. Efferent neurons that innervate the vestibular neuroepithelia are positive for choline acetyltransferase, acetylcholinesterase (AChE), CGRP, and enkephalins [136,
156].
The stimulation of efferent fibers produces complex
effects on the activity of vestibular afferent neurons;
there are reports of increase, inhibition and of mixed
biphasic effects on the electrical discharge of the afferent neurons [25,70,79,192]. The ACh nicotinic re-
124
ceptors (nAChR) in the vestibular neuroepithelia are

formed essentially of 910 subunits [56], although
in adult rats, transcripts encoding the 27 and 2
4 nAChR subunits were found in the vestibular ganglia and vestibular end-organs, while 3, 5-7, 9 and
4 nAChR subunits were expressed in the vestibular
neuroepithelia [8]. In the afferent chalices innervating
type I hair cells nAChRs composed of 4 and 2 subunits have been localized and the efferent innervation
of type II vestibular hair cells utilizes nAChR composed of other subunits [82,197]. Differences in subunit composition or stoichiometry account for the diversity in the physiological and pharmacological properties of nAChRs [82].
In addition to nicotinic receptors, muscarinic receptors (m1, m2 and m5) were expressed in human vestibular afferent neurons, whereas in the rat,
five subtypes of muscarinic receptors (m1m5) were
found [197]. Muscarinic receptors have been the target
of many of the drugs used in the treatment of vestibular
disorders.
Cholinergic input has been identified in all of the
vestibular nuclei [119]. The presence of AChR in the
vestibular nuclei complex (VNC) has been shown by
the AChE staining [155]. Activation of vestibular neurons produced by acetylcholine is similar to that induced by stimulation of the primary afferent neurons; the activation was enhanced by AChE inhibitors
and reduced by mACh antagonists such as scopolamine. Although muscarinic and nicotinic receptors
are present in VNC the muscarinic receptors are expressed in greater density [184]. In the medial nucleus
both types of receptor are located postsynaptically in
the neurons [143].
Among the drugs that modulate cholinergic activity, scopolamine and atropine have the most significant clinical application for the treatment of vestibular
disorders. Other cholinergic drugs like physostigmine
(also known as eserine) and neostigmine have been
used experimentally to induce a motion sickness-like
syndrome.
Scopolamine a nonselective competitive inhibitors
of mACh receptors is a commonly used drug in vestibular disorders. It is effective for the treatment of motion sickness; nevertheless, it has not yet been determined whether its effect takes place at the peripheral or
central vestibular system [86,197]. A recent study indicates that in the treatment of motion sickness, scopolamine is significantly more favorable than placebo and
it has no significant difference in its effectiveness compared to calcium channel antagonists, antihistaminics,
methylscopolamine or a combination of scopolamine

and ephedrine [175]. Due to the short mean life of
scopolamine in plasma and its adverse effects, the clinical use of orally administered scopolamine is limited.
To diminish the incidence of adverse effects, the transdermal dosage by means of patches has been used,
maintaining scopolamine plasma levels approximately
constant over 89 days [131,154].
Contrary to the action of mACh antagonists, the administration of physostigmine, an AChE inhibitor, produced a motion sickness-like syndrome, including nausea, vomiting, discomfort, anxiety, and increases in
ACTH, -endorphin, cortisol and prolactin plasma levels [88]. In fact, physostigmine administration can be
used as a model for the study of motion sickness and
space adaptation syndrome and to detect individuals
susceptibility to the development of these syndromes.
Interestingly, neostigmine (an AChE inhibitor that typically acts on the peripheral nervous system because it
cannot cross the blood-brain barrier) does not have any
significant vestibular effects [128].
Diphenidol (1, 1-diphenyl-1-piperidinebutanol) has
been used for many years in the prevention and symptomatic treatment of peripheral (labyrinthine) vertigo
and associated nausea and vomiting that occur in diverse conditions. In patients with Mnires disease,
double-blind studies showed that use of diphenidol results in better control of symptoms than placebo [63].
Its action mechanism has not been fully elucidated, although anticholinergic effect on mACh receptors (particularly m1, m2, m3 and m4) has been reported [193].
Recently, a series of selective mACh-receptor antagonists based on the diphenidol molecule were synthesized, but no clinical trials have been reported [193].
2.3. Histamine related drugs
The possibility that histamine could act like a neurotransmitter or a neuromodulator at peripheral vestibular end organs was suggested by the finding that astemizole, an H1 -receptor antagonist that does not penetrate
the hematoencephalic barrier, suppresses nystagmus
in patients with chronic dizziness [87]. Later, it was
demonstrated that the H1 , H2 and H3 receptors were
expressed in the vestibular endorgans [29,73,84,187,
190], and H3 and H4 receptor transcripts were found in
the vestibular afferent neurons in rats [42].
Histamine receptors are expressed in the inner ear,
but the source of the endogenous ligands for these receptors is not known. It has been suggested that the
endogenous mediator could be an histamine related
substance such as carnosine or N-acetylhistidine and

that the effects of histamine antagonists occur through
competition with these endogenous analogs of histamine [35,47,84].
In the central nervous system, histamine modulates
the activity of the second order vestibular neurons,
and different effects have been observed depending on
the experimental paradigm used. Immunohistochemical studies reveal a moderately dense histaminergic innervation projecting to the four vestibular nuclei [78,
186,209]. Diverse studies have shown the expression
of histamine receptors in the vestibular nuclei, including H1, H2 and H3 receptors [98,102,209]. In the rat
inferior vestibular nucleus, inhibition of H1 and H2 receptors by the selective antagonists mepyramine and
ranitidine respectively, blocked the histaminergic excitatory effect. The use of H1agonist 2-pyridilethylamine
and H2 agonist dimaprit mimicked the action of histamine. The selective H4 antagonist JNJ7777120 and
H4 agonist VUF8430 had no effect on inferior vestibular nucleus neurons [135].
Among the antihistaminics, betahistine, diphenhydramine (usually in combination with theophylline),
meclizine, its derivate cyclizine, and promethazine
have been the most commonly used in the medical treatment of vertigo. A prospective study in England shows
that, for the treatment of Mnires disease, 92% of
doctors prescribe betahistine [169]. In contrast, in the
United States, the antihistaminics most commonly
used in the treatment of vestibular disorders are diphenhydramine, meclizine (1[(4-chlorophenyl)-phenyl-me
thyl]-4-[(3-methylbenzyl)methyl]pipera-zine), its derivate cyclizine and promethazine. These antihistaminics
are primarily H1 receptor antagonists, but they also
have an anticholinergic effect that is more remarkable
in the case of promethazine [207]. Their actions are
both central and peripheral, although the central action
seems to be essential because antihistaminics that do
not cross the blood-brain barrier are not useful in the
treatment of vertigo.
Betahistine is an analog of histamine that has an antagonistic action on H3 receptors [13]. It also has a partial, weak agonist effect on H1 and H2 receptors [80,
200]. Since its introduction it has been reported that betahistine significantly reduces the incidence and severity of vertigo and decreases the incidence of nausea and
emesis [1,71,97,102,105,126,125]. Controlled studies
demonstrate that betahistine was the most effective
when compared with cinnarizine, clonazepam, flunarizine or Ginkgo biloba. Recent studies indicate that in
Mnires disease patients the use of a combined use
125
of betahistine (32 mg a day for six months) and nimodipine (40 mg a day for six months) showed a significant improvement compared to monoterapy with either drug, thus suggesting that multicomponent therapy may provide a better control over the many symptoms of Mnires disease [127].
In rat brain stem slices, betahistine produced a slight
excitatory action on neurons of the MVN and, in
spite of its apparent weak potency, it significantly reduced the excitatory effect of histamine [83]. Sustained use of betahistine in cats significantly alters histamine turnover in neurons of the tuberomammillary
nucleus [186]. In the vestibular endorgans of rodents
and amphibians, betahistine, as well as its metabolite,
2-(2-aminoethyl) pyridine, diminish the discharge frequency of vestibular afferent neurons [28,29,35]. A recent work from our laboratory showed that betahistine
in the micromolar range, has a significant action on the
resting discharge of the vestibular afferent neurons registered in the isolated rat inner ear [14].
The clinical effects of betahistine have been attributed to the increased blood flow in the inner
ear [117], although also its inhibitory action in primary
afferent neurons and vestibular nuclei neurons may
contribute to reestablish the bilateral gain balance in
the vestibular system [35,73,153,174]. Recently, studies of the expression and the modulation of vestibular primary afferent neuron discharge through the H4
receptor has been studied in the rat inner ear using a
selective H4 antagonist JNJ7777120 and the derivate
compound JNJ10191584. The transcripts of both H3
and H4 receptors were found in the vestibular ganglia [42]. In vitro recordings of the action potential discharge of isolated vestibular neurons showed that both
antagonists produced similar reversible inhibitory effects with IC50 of 9.8 and 16.7 M [42]. Also, studies
using the isolated vestibule of the rat have shown that
JNJ7777120 produced an inhibitory action on vestibular nerve discharge beginning in the nanomolar range
[14, see also Wersinger et al. in this issue of JVR].
These studies demonstrate that H4 receptors mediate
a significant excitatory input to the vestibular afferent neurons that constitute a newly identified target for
vestibular modulation.
2.4. GABA
The possible role of -aminobutyric acid in the
vestibular periphery has been widely discussed without reaching a clear definition of its function in synaptic transmission in vestibular end organs [81,124,195].
126
In contrast, GABAergic innervation of vestibular nuclei has been clearly demonstrated. Pathways from the
cerebellum and commissural fibers from the contralateral nuclei exert a powerful inhibitory input on the
vestibular nuclei, activating both GABAA (ionotropic)
and GABAB (metabotropic) receptors [78,145,165].
Involvement of commissural GABAergic system in
vestibular compensation indicates that, early mechanism of compensation is a down regulation of GABA
receptor in the ipsilesional nucleus neurons [50]. Most
notably it has been found reactive neurogenesis in
the vestibular nuclei after unilateral vestibular neurectomy that lead to GABAergic neurons, along with glial
cells, that seems to significantly contribute to vestibular compensation process [30,49,210].
The GABAA receptor is a pentameric protein which
forms a chloride selective ion channel. Classical benzodiazepines exert a positive allosteric effect by increasing the apparent affinity of channel opening by
GABA [23]. The binding for benzodiazepines is located in a subunit cleft between 1 and 2 subunits
in a position homologous to the agonist binding site
for GABA that is located between 2 and 1 subunits [163]. The pharmacological activity of benzodiazepines is defined according to the selective activation
of different GABAA receptor subtypes [189]. According to their half life benzodiazepiness can be grouped
in short, intermediate and long action. Their principal indications are related to sleep disorders, anxiety
disorders and convulsions [121]. The inhibitory effect
of the benzodiazepines on the electrical activity of the
vestibular nuclei explains its therapeutic effect in vertiginous syndromes, apart from their sedative and anxiolytic action that significantly contributes to the wellbeing of patients [74,207]. A major concern with the
use of benzodiazepines is because of the potential development of use dependence reason why its prescription should be limited to 24 weeks.
GABA related drugs are also useful for the control of nystagmus. Baclofen, a selective agonist of the
GABAB receptor, is commonly used for treatment of
spasticity and recently it was used as adjuvant to treatment of alcohol dependence, it has shown a promising effect in the treatment of uncompensated vestibular asymmetry in animal models [76]. Baclofen presumably acts by enhancing inhibition in vestibular nuclei and related networks, consequently reducing nystagmus in patients with vestibular alterations. Baclofen
also improves periodic alternating nystagmus [208].
The GABA analog gabapentin is an anticonvulsivant
also used for the management, whose mechanism of
action remains not totally clear, but which seems to

be mediated by inhibition of the calcium channel current, thus indirectly reducing neurotransmitter release
and attenuating the postsynaptic excitability [40]. A recent review suggests that typically, acquired pendular
nystagmus may respond to gabapentin or memantine;
downbeat and upbeat nystagmus to aminopyridines;
and periodic alternating nystagmus to baclofen [123,
179].
2.5. Neuropeptides
Like other neurotransmitters and their receptors,
opioid peptides and opioid receptors are expressed in
both the central and the peripheral nervous systems.
Opioid peptides have been detected in auditory and
vestibular efferent neurons, where they colocalize with
the major neurotransmitter, acetylcholine. The Muopioid receptor (MOR) is expressed in Scarpas ganglia and cristae ampullaris of the rat [147]. Opioid receptors exert inhibitory presynaptic action on hair cells
and an excitatory postsynaptic action in afferent neurons. In hair cells, the activation of kappa-opioid receptors (KOR) inhibits the calcium current, decreasing afferent activity. The activation of MOR on afferent neurons potentiates the action of excitatory amino
acids, increasing the afferent activity [194]. The opioids also make an important contribution to the operation of vestibular nucleus neurons [165]. Enkephalincontaining cell bodies and nerve terminals are found in
the medial vestibular nucleus [120]. Enkephalin produced an inhibition of the electrical discharge of neurons of the medial vestibular nucleus, as well as a decrease in its response to glutamate, suggesting that opioids modulate the afferent input to the nuclei [95].
The agonist of the opioid receptor like-1 (ORL-1) nociceptin/orphanin FQ, as well as [D-Ala2, D-Leu5]enkephalin (DADLE: an agonist of the delta opioid receptor), also exerts an inhibitory effect on the electrical activity of MVN neurons. The application of
nociceptin/orphanin FQ in the rat diminishes the gain
of the vestibulo-ocular reflex [182,183].
The finding that opioids affect the excitability of the
inner ear explains why diverse drugs of abuse, such as
heroin and more recently acetaminophen/dihydrocodone combination, can produce significant alterations
in hearing and balance. In fact, there are reports of the
occurrence of a Mnires like-syndrome after the use
of epidural morphine [112]. The combination of fentanyl and droperidol has been used for the treatment of
Mnires disease crises; this mixture has a rapid ac-
tion and results in a complete suppression of vestibular

activity in normal subjects and in those with Mnires
disease [46]. Administration of a single combined
dose of fentanyl and droperidol (droperidol 5 mg, fentanyl 0.1 mg) to patients undergoing acute episodes of
vestibular disease (vestibular neuronitis and Mnires
disease) was effective in the control of nausea, vertigo,
nystagmus, and improves performance in the positive
past-pointing test and the Romberg test [92]. Droperidol alone is also remarkably effective in depressing
vestibular disturbance, regardless of etiology. However, no difference has been found between the therapeutic efficacies of intramuscular injection of droperidol and dimenhydrinate for the treatment of acute peripheral vertigo [85].
Other neuropeptides such as substance P (SP),
CGRP and FMRFamide like peptides have been found
to be expressed in the vestibular endorgans [31,122,
158,191,205]. No precise role of SP has been defined yet. However, two tetrapeptides, PhenylalanineGlycine-Leucine-Methionine-Amide (FGLM-NH2) derived from substance P, and Serine-Serine-Serine-Arginine (SSSR) derived from insulin-like growth factor1 (IGF-1), when locally applied to the inner ear of
guinea pigs, produced an immediate decrease of spontaneous nystagmus and significantly faster recovery of
the vestibulo ocular reflex as compared to control, in
animal model of unilateral vestibular lesion induced by
AMPA [188]. However, the combined use of these two
peptides acting on different targets did not allow to define its individual pharmacological contribution since
IGF-1 activation improves vestibular disorders by itself [129].
The efferent vestibular neurons express both CGRP
and choline acetyltransferase (ChAT) [101,199].
CGRP is a peptide with 37 amino acid residues produced by alternative processing of mRNA transcribed
from the calcitonin gene [203]. In an experimental model of motion sickness it has been found that
the number of CGRP immunoreactive neurons in the
vestibular efferent nucleus and the expression of CGRP
in the VNC increased significantly in rats with motion
sickness compared to that of controls. Anisodamine
(an anticholinergic drug used to treat motion sickness
disorder) decreased the expression of CGRP in the
vestibular efferent nucleus and in the VNC in rats subjected to rotary stimulation. The authors conclude that,
CGRP possibly plays a role in motion sickness and its
mechanism merits further investigation [203].
The tetrapeptide FMRFamide (Phe-Met-Arg-PheNH2) and related peptides RFamide peptides are abun-
127
dant in the invertebrate nervous system functioning

as neurotransmitters and neuromodulators. The related
RFamide peptides (Arg-Phe C-terminal motif) are expressed in the vertebrate nervous system with a significant potential modulatory role in the mammalian brain
and periphery. It has been found that vestibular ganglia neurons are immunoreactive to FMRFamide, and
100 M FMRFamide potentiates the acid sensing ionic
channel (ASIC) currents in isolated afferent neurons
of the rat. FMRFamide also exerts an excitatory effect
on the resting discharge of vestibular afferent neurons
registered in the isolated vestibule preparation of the
rat [122]. Based on these results it has been proposed
that FMRFamide-like peptides may act as a feedback
signal of the afferent neuron activity whose release
may increase the input caused by the ASIC current activation. Also it deserves to mention that the modulation by FMRFamide on the vestibular nerve electrical activity may be due to the interaction between RFpeptide receptors (RF-NH2 R) and opioid receptors,
since in other systems it has been reported that activation of the RF-NH2 R modulates the response of MOR
and KOR [134,149].
2.6. Monoamines
Drugs that affect biogenic amine receptors have
been widely used in the therapy of diverse vestibular disorders; there is a consensus that their effects
are exerted essentially at the central nervous system, not specifically in the vestibular nuclei, although
these have an important noradrenergic, serotonergic
and dopaminergic input [78].
In the vestibular endorgans, D1 and D2 dopamine
receptors have been found in hair cells of rat saccule and utricle and in mouse utricle [48]. The use
of dopamine and D1 (chloro-APB hydrobromide) and
D2 (quinerolane) agonists induced a dose-dependent
and reversible decline in the resting discharge frequency and in the response to glutamatergic agonists
of vestibular afferents in the isolated frog vestibule [9].
The effect of dopamine agonists persists after blocking
synaptic transmission with high Mg2+ solution suggesting that the receptors are located in the vestibular afferent neurons [9]. The 1 -adrenergic receptor
was found in supporting cells of the cristae and maculae of gerbil [59], and the 5-HT1B and 5-HT1D were
found in vestibular ganglion cells of rat and monkey [3,
15]. These findings shown the participation of catecholamines in vestibular neurotransmission [67] and
contribute to the understanding of the mechanism of
action of monoamine related drugs.
128
The presence of dopamine receptors has been suggested in the vestibular nuclei. In the rat medial
vestibular nucleus the basal levels of dopamine and
its metabolite DOPAC have been found to be 9 and
9.2 pmol/mg of protein [36]. Dopamine depolarized
the medial vestibular neurons in the rat, and it has been
suggested the presence of D2 type receptor in medial
vestibular nucleus [64].
In clinics D2 receptor antagonists are used in the vertigo treatment. Droperidol is used in the treatment of
acute peripheral vertigo, sulpiride in the treatment of
spontaneous acute vertigo [36,85], whereas metoclopramide and prochlorperazine are used in the general
vertigo treatment [17,204].
The adrenergic innervations of the vestibular nuclei originates from the locus coeruleus, the superior
vestibular nucleus via the lateral descending bundle
and the rest of vestibular nuclei via the medial descending bundle [160]. Expression of mRNA for the
1A and 1 adrenergic receptor [45,132,133], and immunoreactivity to tyrosine hidroxilase and dopamine-hydroxilase [160] have been demonstrated in all the
nuclei in the rat. Noradrenalin action in vestibular nuclei is complex, while in the superior nucleus its effect is more frequently excitatory and in the rest of
the nuclei the effect is more frequently inhibitory [19].
Inhibition seems to be mediated by 2 -adrenergic receptor [110], and excitation seems to be mediated by
1 - and 1 - adrenergic receptors [146]. Additionally,
noradrenalin modulates the response to glutamate and
GABA [19,43]. Noradrenalin perfusion depressed the
firing induced by glutamate in 40% of the neurons,
enhanced firing in 29%, and produced no change in
31% [19]. In the case of GABA, noradrenalin reduced
the GABA inhibitory action in 42% of the neurons and
increased the GABA action in 40% of the cells [43].
Inhibitors of adrenergic reuptake such as nortriptyline and 1 receptor blocker metoprolol have shown
to be useful in the treatment of migraine-associated
vertigo [61]. The amphetamines improve tolerance
to stimulation with rotations [202]. The use of amphetamines in combination with scopolamine or antihistaminics increased the antivertiginous effect and
reduced the secondary sedation produced by antihistaminics and anticholinergic drugs. Ephedrine (- and
- receptor agonist) seems to be effective in the vertigo
treatment [20].
With respect to serotonin receptor expression in
the vestibular nuclei it was reported the presence of
the 5-HT1A , 5-HT1F , 5-HT2A and 5-HT7 receptor
subtypes [3,4,7,90,91,96]. Serotonergic input to the
vestibular nuclei originates from the raphe nucleus

which sends projections to all vestibular nuclei but especially to the superior and medial nucleus [75]. CGRP
was shown to be colocalized with the 5-HT1F in all the
vestibular nuclei, it was proposed that 5-HT1F agonists
effect in migranous vertigo may be due to attenuation
of CGRP levels [4].
Serotonergic and dopaminergic innervation of the
vestibular nuclei may account for the association that
has been observed between, vestibular alterations, anxiety disorders and migraine [16,62]. Serotoninergic
neurons form part of a network which may have a significant role in the pathogenesis of complex disorders
such as vestibular migraine and they may also participate in the genesis of phobic behavior and elevated
motion sickness discomfort in migraine patients [15].
The co-morbidity of balance disorders and migraine
has been proposed to be due to neuronal pathways
sharing and to the similarity in the receptor expression in vestibular ganglia, trigeminal ganglia and spiral ganglia neurons, thus explaining the auditory and
vestibular symptoms that accompany migraine and the
beneficial effect of triptan derivate drugs in migraine
associated balance disorders [15]. In cases of phobic postural vertigo which is one of the most common causes of vertigo, the selective serotonin reuptake inhibitors (such as sertraline) are commonly used
along with psychotherapy [62,179]. Serotonin depletion (by using a tryptophan free diet or administration of p-chlorophenylalanine) can cause severe dizziness. Dizziness is the most common symptom of selective serotonin reuptake inhibitor discontinuation syndrome, and it is exacerbated by head and eye movements suggesting a vestibular origin [26]. It has been
proposed that abrupt withdrawal from serotonin reuptake inhibitors is likely to cause a decrease in serotonin in the VNC, which could disrupt the function of
nucleus neurons bilaterally, causing dizziness without
vertigo [166].
Of the serotoninergic drugs, the triptans rizatriptan
and zolmitripan (5-HT1B/1D receptor agonists) have
shown to be efficient to prevent motion sickness in patients with migraine-associated vertigo [115], methysergine (5-HT2 antagonist) has been used in the treatment of the nucleoreticular vestibular syndrome [107],
whereas granisetron and ondansetron (5-HT3 receptor
antagonists) are used in the treatment of vertigo [204].
3. Drugs acting on voltage-gated ionic channels
The definition of an important set of channelopathies
that affect inner ear function and the identification of
the functional roles of diverse subtypes of ion channels

in the inner ear have allowed substantial expansion of
the use of drugs with effects on these membrane proteins [65]. For reviews of ionic channels on vestibular
endorgans and on vestibular nuclei see [53,54,100].
3.1. Ca2+ channels
The participation of calcium channels in neurotransmitter release at synaptic terminals constitutes the primary therapeutic target of calcium channel blockers;
although the calcium-activated potassium current may
also be a significant target contributing to the action of
these drugs [52]. Neurotransmitter release in hair cells
is mediated by high voltage-activated L-type calcium
channels (CaV 1.3) that can be blocked by dihydropyridines [6,12,18,141]. In the afferent neurons calcium
channels (probably L-, N- and T-type) participate in
the generation of repetitive action potential discharge
and in the control of the excitability of afferent neurons by the activation of the calcium-activated potassium current [111]. The calcium currents of the afferent neurons also participate in neurotransmitter release
at the vestibular nuclei, probably through N- or P/Qtype channels [34].
Neurons of the vestibular nuclei express high threshold L- and N-type calcium channels as well as low
threshold T-type calcium channels [161,162]. Hence,
the calcium channel blockers affect the input and output of information of the vestibular nuclei. Depending on the functional role of the subtypes of channel in each synapse, the effect of some blockers could
be greater than others, leading to selectivity [167]. At
synapses in the central nervous system, the calcium
channels that participate in neurotransmitter release are
N- or P/Q-type. These channels are not blocked by the
dihydropyridines.
The most commonly used calcium channel blockers for the management of vestibular disorders are nimodipine, nitrendipine (a dihydropyridine with long
lasting effect) and verapamil. Other long lasting dihydropyridines such as amlodipine, felodipine, nicardipine and nifedipine are seldom used [74,106,159]. The
piperazine derivates cinnarizine and flunarizine, both
of which have an antihistaminic action, have been
widely used in the treatment of vestibular disorders.
Cinnarizine, besides its L-type calcium channel blocking action [12], acts as a blocker of the pressuresensitive potassium channels. This may be relevant in
the vestibule, since this last type of channel can be
activated when inner ear endolymphatic hydrops de-
129
velops [51,52]. In addition, cinnarizine and flunarizine

have antihistaminic action (acting on H1 receptor) and
potential (although very weak) nicotinic receptor antagonism. Disappointingly, no studies have evaluated
the exact role of these actions in the therapeutic effect
of these drugs [150].
Nimodipine and nitrendipine are L-type calcium
channel blockers that inhibit the calcium current and
neurotransmitter release in hair cells [6,141]. Verapamil, has also been successfully used in the management of vestibular migraine syndrome [151]. Also,
there are reports that suggest a significant effectiveness
of cinnarizine on the management of vertigo of peripheral origin [144]. Gabapentin (Neurontin), which was
originally thought to act exclusively on GABA receptors, also has a blocking effect on calcium channels,
specifically binding to the 2 subunit of these channels [105]. This drug has been used in the treatment of
vertigo and certain types of nystagmus of central origin [176].
Independently of their effects in the vestibular system, the calcium channel blockers have a negative inotropic effect and antimigraine action. Calcium channel blockers also modify diverse cellular signals related to apoptosis. In fact, because patients with
vestibular alterations have a high prevalence of migraine, the blocking of calcium channels (particularly
by verapamil and nimodipine) offers an additional advantage because of its anti migraine effect [151].
3.2. Na+ channels
Diverse types of voltage gated sodium channels
(Nav ) are expressed in the inner ear neuroepithelia [113]. Among them, the TTX-sensitive type channels play a fundamental role in the action potential
discharge in afferent neurons and in the neurons of
vestibular nuclei. Sodium currents participate in the
ontogeny of hair cells and mediate the generation of
the action potential in neurons, and participate in the
setting of afferent neuron discharge regularity [113].
It has been shown that the calyx endings express the
Nav 1.5 in the inner synaptic zone (Domain 1 according to [113]), while the Nav 1.6 is located in the heminode of dimorphic but not calyx neurons (Domain 4
according to [113]). The Nav 1.6 is known for its capacity to generate persistent Na+ currents in axonal
initial segments and for its role in the regulation of
neuronal spike timing. The pharmacological modification of sodium channel produces significant changes in
both the excitability and discharge pattern of the af-
130
ferent neurons and of vestibular nucleus neurons [38,

173].
Also it has been found that afferent neurons express a potassium current activated by intracellular
sodium [32], which may be modulated by subtle channels in the Na+ current amplitude, thus playing a potential role in the control of afferent neuron excitability, and it opens the potential use of bepridil derivatives in the management of vestibular disorders [109].
In rats experimental transtympanic infusion of lidocaine produces a vigorous spontaneous nystagmus that
reaches its maximum after 20 min of drug administration [114].
Clinical reports indicate that transtympanic infusion
of lidocaine with dexamethasone could have a significant beneficial effect in the management of acute vertigo and in the long-term management of patients with
Mnires disease. With the use of transtympanic lidocaine in a group of 113 patients, 83% experienced an
immediate lightening of the sensation of fullness of the
ear and dizziness; a year after treatment 69% of these
patients still showed remission of symptoms [157].
Nevertheless, in these studies lidocaine was combined
with corticoids; therefore, it is difficult to judge which
drug caused the effect. More recently, the use of transtympanic lidocaine in treatment of Mnires disease
has been reevaluated. Transtympanic instillation of lidocaine with furfuryladenine produced a remarkable
improvement in the vestibular symptom [2].
Carbamazepine, an anticonvulsant structurally similar to tricyclic antidepressants, whose action is due
to a reduction of neuronal excitability produced by
stabilization of the inactivated state of the voltagedependent sodium channel, has been used in the treatment of tinnitus. In tinnitus induced by salicylates in
rat models, low doses of carbamazepine suppressed the
behavior associated to tinnitus [211]. Carbamazepine
and oxocarbazepine have also been used in the treatment of vertigo and particularly in paroxystic disorders. In general, agents used for the treatment of
epilepsy like topiramate, lamotrigine and valproate are
useful in the treatment of vertigo of different origins [74,93,99].
3.3. K+ channels
Potassium channels exhibit the greatest diversity
among ionic channels. They play a significant role in
many channelopathies, and many drugs act on these
channels. However, in the management of vestibular disorders, only 3, 4-diaminopyridine, a blocker of
voltage-activated K+ channels (Kv1), has been used

for the management of downbeat nystagmus [177]. 3,
4-diaminopyridine produced a significant control of
the nystagmus that appears in patients with type 2
episodic ataxia (EA2) [180], presumably by increasing the excitability of cerebellar Purkinje cells increasing the action potential duration and action potential
after-hiperpolarization [68,89]. It has been proposed
that aminopyridines could have abundant utility in diverse oculomotor disorders and in disorders of cerebellar origin [179].
Our research group has shown that low threshold
voltage-activated potassium current has a significant
role in the control of the activity of vestibular afferent neurons [137,139]. This current is modulated by
the activation of mACh receptors (thus, it is called
the M-current). The functional role of the M-current
in vestibular afferent neurons allows us to suggest the
use of retigabine, an activator of the M-current, and of
linopirdine, a blocker of the M-current, as drugs with
significant potential for the management of vestibular
disorders that may result from an imbalance of the afferent neuron activity incoming from each vestibule.
4. Conclusion
A lot of work has been done to study the action
mechanism of drugs on voltage and chemically gated
channels. However, to understand the pharmacological action of many of the drugs used in clinics a systemic perspective is required. This implies not only to
consider the interactions that drugs may have at the
vestibular system, but also to consider their possible
central nervous system effects. Clinicians deals with
human subjects, not with in vitro animal preparations
like the isolated vestibule, or with brain slices as commonly used in research laboratories. So, it is important
to consider the action on other non-vestibular targets,
either in the nervous system or in other organs such
as the heart. By practical reasons this work restricts to
the discussion of vestibular system targets, where most
of the drugs used in clinic may have both peripheral
and central actions and a plethora of effects at the central nervous system. In spite of the complexity of the
mechanisms involved in their actions the whole analysis of their effects may allow to deepen our understanding of vestibular alterations and to develop a broader
perspective of the origins of vestibular pathology,. In
fact a network perspective has been proposed as the basis for a new rationale in therapeutics [55]. Avoiding
reductionistic explanations and recognizing that multiple and sometimes pleiotropic effects are much more
common, and at times more desirable than the magic
bullets supposedly targeting a single cellular receptor.
Although a large pharmacological arsenal of drugs
is available for the treatment of vestibular disorders,
the complexity of this organ and the adaptive processes
that compensate for vestibular deficits thereby producing a complex evolution of signs and symptoms, makes
it difficult to evaluate the effectiveness of commonly
used drugs in the treatment of vestibular disorders. The
critical analysis of the literature reveals that there is a
significant lack of information defining the real utility
of diverse drugs used in clinical practice. The development of basic studies addressing drug actions at the
molecular, cellular and systems level, combined with
reliable and well controlled clinical trials, would provide the scientific basis for new strategies for the treatment of vestibular disorders.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
Acknowledgments
[15]
E.S.M received a fellowship for doctoral studies

from CONACyT 206608. This work was partially supported by grant PIFI-2011 and the National Council of
Science and Technology of Mxico (CONACyT grant
167052) to E.S. and by Vicerrectoria de Investigacin
(VIEP-BUAP)-CONACyT grants to RV and ES.
[16]
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[18]
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Neuropharmacological basis of vestibular

Meritorious Autonomous University of Puebla

Meritorious Autonomous University of Puebla

93 PUBLICATIONS 774 CITATIONS

81 PUBLICATIONS 850 CITATIONS

Available from: Enrique Soto

Journal of Vestibular Research 23 (2013) 119137

Neuropharmacological basis of vestibular

Received 23 November 2012

c 2013 IOS Press and the authors. All rights reserved

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

2. Drugs with effects on receptors for

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

tamine H1 , H2 and H3 receptors [24], serotonine 5HT1

Vestibular nuclei neurons also produce neuroactive

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

case of coreiform manifestations related to its use has

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

Recently, neramexane which is an amino-alkylcyclohexane derivate that acts as a nicotinic receptor

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

ceptors (nAChR) in the vestibular neuroepithelia are

methylscopolamine or a combination of scopolamine

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

substance such as carnosine or N-acetylhistidine and

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

action remains not totally clear, but which seems to

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

tion and results in a complete suppression of vestibular

dant in the invertebrate nervous system functioning

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

vestibular nuclei originates from the raphe nucleus

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

the functional roles of diverse subtypes of ion channels

velops [51,52]. In addition, cinnarizine and flunarizine

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

ferent neurons and of vestibular nucleus neurons [38,

voltage-activated K+ channels (Kv1), has been used

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

E.S.M received a fellowship for doctoral studies

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

International Union of Pharmacology. XIII. Classification of

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

A.P. Nicholas, V. Pieribone and T. Hkfelt, Distributions

produced by [D-Met2 ]-FMRFamide in mice, Neuropeptides

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

effects of acetylcholine agonists and antagonists, Brain Res

E. Soto et al. / Neuropharmacological basis of vestibular system disorder treatment

mechanism of action of anti-histaminergic drugs in vertigo

T.P. Zajonc and P.S. Roland, Vertigo and motion sickness.

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