<p>Primary hippocampal neurons were cultured with 10 nM PACAP or 2 nM BDNF in the presence ... more <p>Primary hippocampal neurons were cultured with 10 nM PACAP or 2 nM BDNF in the presence or absence of 200 nM K252a for 3 DIV and double-immunostained for pNF and MAP2. Representative pNF- (red) and MAP2- (green) immunostained images of neurons (A), axon length (B), and dendrite length (C) were shown. Values represent mean ± SEM of 60 neurons from three independent experiments. **<i>P</i> < 0.01 vs. control, <sup>##</sup><i>P</i> < 0.01 vs. without K252a, two-way ANOVA followed by Tukey-Kramer test. Scale bar, 20 μm.</p
Pituitary adenylate cyclase-activating polypeptide (PACAP) has been postulated to be involved in ... more Pituitary adenylate cyclase-activating polypeptide (PACAP) has been postulated to be involved in the development of psychiatric disorders. PACAP-deficient mice show behavioral and neurophysiological abnormalities including novelty-induced hyperlocomotion, emotional lability, depression-like behaviors, and memory impairments that are ameliorated with atypical antipsychotic drugs (serotonin–dopamine antagonists). Targeted deletion of the PACAP receptor PAC1 leads to several of these abnormalities. Genetic studies in humans suggest that single nucleotide polymorphisms and copy number variations of the PACAP and/or PACAP receptor genes may be a genetic risk factor for psychiatric disorders including schizophrenia. Although these findings in patients need further replication and the exact mechanisms for PACAP-dependent psychomotor regulation remain to be determined, several potential mechanisms have been proposed. Thus, the convergent evidence from animal models and humans suggest that PACAP signaling can be an intrinsic regulator of psychoneurological functions and an attractive therapeutic target for the disorders.
The present study examines the effect of the cognition enhancer (1R)-1benzo[b]thiophen-5-yl-2-[2-... more The present study examines the effect of the cognition enhancer (1R)-1benzo[b]thiophen-5-yl-2-[2-(diethylamino)ethoxy]ethan-1-ol hydrochloride (T-588) on neuronal injury induced by serum deprivation or amyloid-b protein (Ab). T-588 protected partially against neuronal injury induced by serum deprivation or Ab in cultured cortical neurons. T-588 did not affect the phosphorylation of extracellular signal-regulated kinase (ERK) in cortical neurons and SH-SY5Y cells. These results suggest that T-588 has a protective effect in neuronal injury models and the effect is not mediated by an ERK signal pathway.
The present study examined the effect of zotepine, an atypical antipsychotic, on the in vivo rele... more The present study examined the effect of zotepine, an atypical antipsychotic, on the in vivo release of monoamines in the prefrontal cortex of rats using microdialysis. Local perfusion of zotepine at 10 μM increased extracellular levels of serotonin (5-HT), as well as dopamine and noradrenaline, in the prefrontal cortex. However, systemic administration of zotepine did not affect 5-HT release, although it increased the dopamine and noradrenaline release. These results suggest that the prefrontal 5-HT system does not contribute to the antidepressant effect of zotepine. The difference in the effect of zotepine between local and systemic treatment is discussed.
Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is cha... more Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A nonstimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclaseactivating polypeptide (PACAP)-deficient (PACAP À/À) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP À/À mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP À/À mice compared to wildtype mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP À/À mice. Our current study suggests that PACAP À/ À mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP À/À mice on behaviors are discussed.
Metabotropic glutamate 2/3 receptor (mGluR2/3) agonists inhibit amphetamine-and phencyclidine-ind... more Metabotropic glutamate 2/3 receptor (mGluR2/3) agonists inhibit amphetamine-and phencyclidine-induced hyperactivity. Moreover, they ameliorate the deficits of attention and working memory induced by N-methyl-Daspartate (NMDA)-receptor antagonists. These findings suggest that activation of mGluR2/3 has a therapeutic potential for the treatment of schizophrenia (1). However, these models are not concerned with the environmental or developmental perspective in the etiology of schizophrenia. Rearing in social isolation from early life causes abnormal behaviors such as hyperactivity, aggressive behavior, deficits of prepulse inhibition (PPI), and cogni-tive impairments in rats and mice. Many of these behaviors strongly resemble core symptoms of schizophrenia (2). Moreover, anti-psychotic drugs such as risperidone and clozapine attenuate isolation rearing-induced aggressive behavior and PPI deficits in mice (3). We have recently shown that binding of the mGluR2/3 antagonist [ 3 H]LY341495 in the prefrontal cortex and hippocampus was increased by isolation rearing in mice (4). This suggests that dysfunction of the glutamatergic system including mGluR2/3 contributes to the mechanisms for isolation rearing-induced abnormal behaviors. To study the therapeutic potential of mGluR2/3 ligands for psychiatric disorders, this study examined the effect of MGS0028, a potent and selective mGluR2/3 agonist (5, 6), on the abnormal behaviors of isolation-reared mice. The experimental procedures concerning the use of
The behavior of isolation-reared mice has not yet been studied in the staircase test. The present... more The behavior of isolation-reared mice has not yet been studied in the staircase test. The present study examined the effects of anxiolytic or anxiogenic agents and isolation rearing on the behavior of ddY (outbred) strain mice in the staircase test. Diazepam and phenobarbital increased the number of steps climbed, but did not affect rearing behavior in group-reared mice. FG-7142, a benzodiazepine inverse agonist, significantly increased the number of rearing with no changes in the number of steps climbed in group-reared mice. Methamphetamine increased the number of steps climbed and decreased the number of rearing in group-reared mice. Although isolation-reared mice showed hyperactivity, there was no difference in locomotor activity for the test period of 3 min between isolation-and group-reared mice. Under these conditions, isolation rearing increased the numbers of steps climbed and rearing compared to group-reared controls. Microanalysis of locomotor patterns of group-reared mice in the staircase test showed that anxiolytic drugs increased the number of climbing to the top step of the staircase and methamphetamine increased the number of climbing to the first to third step. These results suggest that isolation rearing causes an anxiety-like state with increased exploratory behavior in mice.
Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induce... more Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induced hyperlocomotion. The mechanism for the antipsychotic effect of mGlu2/3 receptor agonists was studied in a hypoglutamatergic model, but not a hyperdopaminergic model. To study the mechanism for the antipsychotic effect of the agonist in the hyperdopaminergic model, this study examined the effects of the selective mGlu2/3 receptor agonist MGS0028 on methamphetamine-induced hyperlocomotion and the increases in extracellular levels of serotonin, dopamine, noradrenaline, and glutamate in the prefrontal cortex and nucleus accumbens of mice. Systemic administration of MGS0028 attenuated methamphetamine-induced hyperlocomotion in a dose-dependent manner. Microdialysis studies showed that MGS0028 significantly inhibited methamphetamine-induced increases in the extracellular serotonin, but not dopamine and noradrenaline, levels in the prefrontal cortex, and it did not affect methamphetamine-induced increases in the extracellular amine levels in the nucleus accumbens. Methamphetamine did not affect the glutamate release in the prefrontal cortex and nucleus accumbens. Local application of MGS0028 into the prefrontal cortex also attenuated methamphetamine-induced hyperlocomotion and increases in the extracellular serotonin levels in the prefrontal cortex. Moreover, MGS0028 did not affect methamphetamine-induced hyperlocomotion in the mice pretreated with p-chlorophenylalanine, a serotonin synthesis inhibitor. Activation of prefrontal mGlu2/3 receptors inhibits the psychomotor stimulant effect of methamphetamine in mice, and the prefrontal serotonergic system may be involved in this effect. The finding provides evidence that prefrontal mGlu2/3 receptors are functionally coupled with the serotonergic system.
Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor act... more Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor activity known as behavioral sensitization. We have recently shown that chronic METH enhanced METH challenge-induced increase in 5-HT levels in the prefrontal cortex and that 5-HT(1A) receptor activation attenuated this neurochemical sensitization as well as behavioral sensitization. This study examined whether the nonselective 5-HT(2) receptor antagonist, ritanserin affects METH-induced behavioral and neurochemical sensitization in mice. Ritanserin at doses of 1 and 3 mg/kg inhibited the development and expression of METH-induced behavioral sensitization in a dose-dependent manner. Furthermore, chronic administration of ritanserin for a week attenuated the maintenance of behavioral sensitization, indicating the improvement of established behavioral sensitization. Microdialysis analysis showed that chronic ritanserin inhibited the neurochemical sensitization that chronic METH enhanced METH challenge-induced increase in extracellular 5-HT levels in the prefrontal cortex. Furthermore, acute ritanserin inhibited METH challenge-induced increase in extracellular 5-HT but not DA levels in the prefrontal cortex. These results suggest that 5-HT(2) receptors are involved in METH-induced hyperactivity and behavioral sensitization in mice.
s / Neuroscience Research 68S (2010) e335–e446 e367 tions. Genetic tracing for DAergic lineage us... more s / Neuroscience Research 68S (2010) e335–e446 e367 tions. Genetic tracing for DAergic lineage using TH-Cre;Rosa26R-CFP mice revealed that the olfactory manipulations drastically altered the number of DAergic PGCs. Furthermore, we tested whether the positions that had lost PGCs were refilled with newly added PGCs. Interestingly, after the selective elimination of DAergic PGCs by in vivo two-photon laser ablation, same subtype of the PGCs was added into their positions. These observations suggest that the turnover dynamics of DAergic PGCs are dependent on the their spatio-temporal context and olfactory experience. doi:10.1016/j.neures.2010.07.1624 P3-e12 Injury-induced activation of cell proliferation and migration in the adult zebrafish telencephalon Norihito Kishimoto 1,2 , Kohei Shimizu 1, Kazunobu Sawamoto 1 1 Department of Dev and Regene Biol., Nagoya City University, Nagoya 2 Center for Integrated Medical Research, Keio University, Tokyo, Japan Recent studies have shown that adult neurogenesis is conserved in various vertebrates, including mammals, bird and reptiles. In the adult mammalian brain, newborn neurons in the subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) into the olfactory bulb (OB). On the other hand, they migrate toward injured area in injured brain. To provide new insights into the cellular and molecular mechanisms of adult neurogenesis, we have studied neuronal production and migration in zebrafish, in which powerful genetic approaches and in vivo imaging techniques are available. Our recent morphological studies have indicated that the adult fish brain possesses proliferating zone in the VZ and RMS-like route similar to those in rodents. Here, we provide direct evidence that neuronal progenitors migrate in the adult fish brain using a transgenic zebrafish line that expresses GFP under the control of the neuogenin1 promoter that is active in neuronal progenitor cells. In addition, we generated telencephalon injury in the adult zebrafish telencephalon. Lesion of adult zebrafish telencephalon stimulated cell proliferation in the VZ and the vicinity of the injured site, suggesting that the activation of the SVZ by brain injury is a common feature in vertebrates and that the adult zebrafish telecephalon injury is useful as a new model to investigate the molecular and cellular processes underlying neuronal regeneration. doi:10.1016/j.neures.2010.07.1625 P3-e13 Administration of NMDA receptor antagonist causes down-regulation of DISC1 expression and over migration of newly generated neurons in the adult hippocampus Takashi Namba 1,2 , Kotaro Hattori 3, Hiroshi Kunugi 3, Kozo Kaibuchi 1, Shigeo Uchino 2, Shinichi Kohsaka 2 1 Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Japan 2 Department of Neurochemistry, National Institute of Neuroscience, Tokyo, Japan 3 Department of Mental Disorder Research, National Institute of Neuroscience, Tokyo, Japan New neurons are continuously generated through out life in the hippocampus. Newly generated neurons migrate short distance and are integrated into pre-existing neuronal circuit. However, the extra cellular signals which regulate the neuronal migration are not fully understood. Here we report that NMDA receptor (NMDA-R) signaling is involved in cellular migration and proper positioning of newly generated neurons in the adult hippocampus. An intraperitoneal injection with an NMDA-R antagonist, memantine or CPP, into adult male mice caused aberrant positioning of Dcx-positive immature neurons. BrdU labeling analysis revealed that NMDA-R antagonist caused an over migration of newly generated neurons. Using a quantitative real-time PCR analysis, we examined the expression of Disrupted-In-Schizophrenia 1 (DISC1) that has been identified as a candidate susceptibility gene for major psychiatric disorders such as schizophrenia, because it has been known that DISC1 is one of the important molecules regulating migration of newly-generated neurons in the adult hippocampus. The expression of DISC1 in the dentate gyrus was reduced by NMDA-R antagonist-injection in a dose-dependent manner. In contrast, the expression of the DISC1interacting molecules, Lis1, NDEL1 and Girdin, was not affected by the NMDA-R antagonist-injection. These results suggest that the NMDA-R signaling affects the migration of newly generated neurons via regulating the expression of DISC1. doi:10.1016/j.neures.2010.07.1626 P3-e14 Investigating the roles of purinergic signaling in adult neurogenesis Satoshi Suyama , Takehiko Sunabori, Hideyuki Okano Department of Physiology, Keio University, School of Medicine, Japan It was long believed neurogenesis never occurs in the adult mammalian central nervous system (CNS). In the late 1990s, however, persistent neurogenesis was shown to occur in two restricted areas in adult mammalian brain: subventricular zone (SVZ) and subgranullar zone (SGZ) of the hippocampus. Within these neurogenic…
Biochemical and Biophysical Research Communications, Mar 1, 2015
Systematic and simultaneous analysis of multiple cell types in the brain is becoming important, b... more Systematic and simultaneous analysis of multiple cell types in the brain is becoming important, but such tools have not yet been adequately developed. Here, we aimed to generate a method for the specific fluorescent labeling of neurons and astrocytes, two major cell types in the brain, and we have developed lentiviral vectors to express the red fluorescent protein tdTomato in neurons and the enhanced green fluorescent protein (EGFP) in astrocytes. Importantly, both fluorescent proteins are fused to histone 2B protein (H2B) to confer nuclear localization to distinguish between single cells. We also constructed several expression constructs, including a tandem alignment of the neuron- and astrocyte-expression cassettes for simultaneous labeling. Introducing these vectors and constructs in vitro and in vivo resulted in cell type-specific and nuclear-localized fluorescence signals enabling easy detection and distinguishability of neurons and astrocytes. This tool is expected to be utilized for the simultaneous analysis of changes in neurons and astrocytes in healthy and diseased brains.
Mice lacking the PACAP gene (PACAP(-/-)) display psychomotor abnormalities such as novelty-induce... more Mice lacking the PACAP gene (PACAP(-/-)) display psychomotor abnormalities such as novelty-induced hyperactivity and jumping behavior, and they show different responses to amphetamine, a typical psychostimulant. The present study examined the possible role of endogenous PACAP in methamphetamine (METH)-induced hyperactivity and behavioral sensitization. The locomotor activity of hyperactive PACAP(-/-) mice was measured using the infrared photocell beam detection system, Acti-Track, after a habituation period. Single administration of METH (1 and 2mg/kg) caused a robust increase in locomotor activity of mice, but this effect did not differ between wild-type and PACAP(-/-) mice. Repeated administration of METH (1mg/kg) for 7 days enhanced METH-induced hyperactivity, and this sensitization was observed even when withdrawn for 7 days. There was no difference in the degree of development and expression of METH-induced behavioral sensitization between wild-type and PACAP(-/-) mice. In addition, there was no difference in METH-induced increases in extracellular serotonin and dopamine levels in the prefrontal cortex of the normal and sensitized mice between the two groups. These results suggest that endogenous PACAP is not involved in the locomotor stimulant activity of acute METH and repeated METH-induced behavioral and neurochemical sensitization.
This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluv... more This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice. The effect of fluvoxamine was attenuated by the serotonin type 1A receptor antagonist WAY100635 at 1 mg/kg, while it was enhanced by the antagonist at 0.1 mg/kg. Fluvoxamine (30 mg/kg) and WAY100635 (0.1 and 1 mg/kg) did not affect spontaneous locomotor activity. These results suggest that the effect of fluvoxamine is mediated by postsynaptic serotonin type 1A receptors and it is enhanced by an inhibition of presynaptic serotonin type 1A receptors.
Pharmacology, Biochemistry and Behavior, Sep 1, 2006
Repeated intermittent administration of psychostimulants causes behavioral sensitization in roden... more Repeated intermittent administration of psychostimulants causes behavioral sensitization in rodents. Previous studies using serotonin (5-HT) receptor ligands show that the 5-HT system is involved in cocaine-induced behavioral sensitization in rats, but the role of the 5-HT system has not been studied in mice. The present study examined the effects of the 5-HT(1A) receptor agonist osemozotan, the 5-HT(2) receptor antagonist ritanserin and the 5-HT(3) receptor antagonist azasetron on cocaine-induced behavioral sensitization in male ddY mice. Repeated administration of cocaine for 7 days enhanced cocaine-induced locomotor activity, and this sensitization was observed even after withdrawal for 7-14 days. Cocaine-induced behavioral sensitization after a 7-day withdrawal was significantly reduced with the coadministration of osemozotan, ritanserin or azasetron with cocaine repeatedly for 7 days. A single injection of osemozotan or ritanserin before cocaine challenge also reduced repeated cocaine-induced behavioral sensitization. However, none of these ligands inhibited cocaine-induced behavioral sensitization, when each drug was administered for 7 days after repeated cocaine administration. These results suggest that the central 5-HT system plays a role in the development and expression, but not maintenance, of behavioral sensitization in cocaine-treated mice.
Previous studies suggest that metabotropic glutamate 2/3 receptors are involved in psychiatric di... more Previous studies suggest that metabotropic glutamate 2/3 receptors are involved in psychiatric disorders. In this study, we examined the effects of the selective metabotropic glutamate 2/3 (mGlu2/3) receptor agonist MGS0028 on behavioral abnormalities in mice lacking the pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental model of psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder. We found that PACAP-deficient mice showed impairments in the novel object recognition test and these impairments were improved by MGS0028 (0.1 mg/kg). Similarly, MGS0028 improved hyperactivity and jumping behaviors, but did not reverse increased immobility times in the forced swim test in PACAP-deficient mice. These results suggest that MGS0028 may be a potential, novel treatment for psychiatric disorders.
Post-weaning social isolation in rodents induces behavioral alterations, including hyperlocomotio... more Post-weaning social isolation in rodents induces behavioral alterations, including hyperlocomotion, depression-and anxiety-like behaviors, aggression, and learning and memory deficits. These behavioral abnormalities may be related to the core symptoms in patients with neuropsychiatric disorders, such as schizophrenia and depression. In view of the recent studies that the group II metabotropic glutamate receptor (mGluR2/3) is involved in neuropsychiatric disorders, the present study examined the effect of isolation rearing on the binding of the mGluR2/3 antagonist [ 3 H]LY341495 to mGluR2/3 in the mouse brain by in vitro autoradiography. The [ 3 H]LY341495 binding in the prefrontal cortex, cerebral cortical layers IeIII and hippocampus was significantly increased by rearing in social isolation while the binding in other brain regions was not altered. A saturation binding study of hippocampal membranes from isolation-reared mice revealed that the B max value increased significantly without any changes in the K d value. Moreover, the mGluR2/3 antagonist MGS0039 (1.0 mg/kg, intraperitoneally) decreased the immobility time of isolation-reared mice in the forced swim test. These results suggest that isolation rearing causes an increase in mGluR2/3 densities in the prefrontal cortex and hippocampus and that the increased receptor function may contribute to pathogenic mechanisms for depression-like behavior of the isolation-reared mice.
The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive... more The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive effect of (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3- benzodioxole HCl (MKC-242), a 5-HT(1A) receptor agonist. MKC-242 (0.1-1.0 mg/kg, p.o.) selectively reduced isolation-induced aggressive behavior in a dose-dependent manner. Flumazenil (10 mg/kg, i.p.) antagonized the antiaggressive effects of MKC-242 and diazepam, although it alone did not affect the behaviors of isolated mice. These findings suggest that a gamma-aminobutyric acid(A) (GABA(A)) receptor system is involved in the antiaggressive effect by 5-HT(1A) receptor activation.
Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activi... more Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play key roles as the neural substrates mediating behavioral sensitization, but the role of the serotonin (5-HT) system in the sensitization is not fully elucidated. We have recently demonstrated that osemozotan, a specific 5-HT 1A-receptor agonist, and ritanserin, a 5-HT 2-receptor antagonist, inhibited the expression and development of both methamphetamine-and cocaine-induced behavioral sensitization in mice and that these drugs attenuated the maintenance of behavioral sensitization of methamphetamine, but not that of cocaine. We also found that azasetron, a 5-HT 3-receptor antagonist, inhibited the expression and development of the sensitization induced by methamphetamine and cocaine, respectively. Neurochemical studies using a microdialysis technique showed that repeated methamphetamine enhanced the methamphetamine-induced increase in 5-HT release in the prefrontal cortex. The sensitization of 5-HT release in methamphetamine-treated mice was attenuated by osemozotan and ritanserin. These findings suggest that the 5-HT system plays an important role in methamphetamine-and cocaine-induced behavioral sensitization in mice and imply that 5-HT 1A-receptor agonists and 5-HT 2-receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.
Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activities includi... more Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activities including modulation of synaptic plasticity and memory, hippocampal neurogenesis, and neuroprotection, most of which are shared with brain-derived neurotrophic factor (BDNF). Therefore, the aim of this study was to compare morphological effects of PACAP and BDNF on primary cultured hippocampal neurons. At days in vitro (DIV) 3, PACAP increased neurite length and number to similar levels by BDNF, but vasoactive intestinal polypeptide showed much lower effects. In addition, PACAP increased axon, but not dendrite, length, and soma size at DIV 3 similarly to BDNF. The PACAP antagonist PACAP6-38 completely blocked the PACAP-induced increase in axon, but not dendrite, length. Interestingly, the BDNF-induced increase in axon length was also inhibited by PACAP6-38, suggesting a mechanism involving PACAP signaling. K252a, a TrkB receptor inhibitor, inhibited axon outgrowth induced by PACAP and BDNF without affecting dendrite length. These results indicate that in primary cultured hippocampal neurons, PACAP shows morphological actions via its cognate receptor PAC 1 , stimulating neurite length and number, and soma size to a comparable extent as BDNF, and that the increase in total neurite length is ascribed to axon outgrowth.
Coadministration of atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) e... more Coadministration of atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) enhances the release of monoamines such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the prefrontal cortex. To clarify the role of DAD 2/3 receptors in the combination effect, we examined the effects of coadministration of the selective DAD 2/3 antagonist sulpiride and the SSRI fluvoxamine on amine neurotransmitter release in rat prefrontal cortex. Sulpiride (10 mg/kg, i.p.) and fluvoxamine (10 mg/kg, i.p.) alone did not affect extracellular DA levels, while their coadministration caused a significant increase in DA levels. Sulpiride alone did not affect extracellular levels of 5-HT and NE in the prefrontal cortex, while fluvoxamine alone caused a marked increase in 5-HT levels and a slight increase in NE levels. Sulpiride did not affect the fluvoxamine-induced increases in extracellular levels of 5-HT and NE. The DAD 2/3 antagonist haloperidol (0.1 mg/kg) in combination with fluvoxamine also caused a selective increase in extracellular DA levels in the cortex. Coadministration of sulpiride and fluvoxamine did not affect extracellular DA levels in the striatum. Combination of systemic sulpiride and local fluvoxamine did not increase the DA levels, but that of systemic fluvoxamine with local sulpiride increased. The combination effect in increasing prefrontal DA levels was antagonized systemically, but not locally, by the 5-HT 1A antagonist WAY100635 at a low dose. These findings suggest that the combination of prefrontal DAD 2/3 receptor blockade and 5-HT 1A receptor activation in regions other than the cortex plays an important role in sulpiride and fluvoxamine-induced increase in prefrontal DA release.
<p>Primary hippocampal neurons were cultured with 10 nM PACAP or 2 nM BDNF in the presence ... more <p>Primary hippocampal neurons were cultured with 10 nM PACAP or 2 nM BDNF in the presence or absence of 200 nM K252a for 3 DIV and double-immunostained for pNF and MAP2. Representative pNF- (red) and MAP2- (green) immunostained images of neurons (A), axon length (B), and dendrite length (C) were shown. Values represent mean ± SEM of 60 neurons from three independent experiments. **<i>P</i> < 0.01 vs. control, <sup>##</sup><i>P</i> < 0.01 vs. without K252a, two-way ANOVA followed by Tukey-Kramer test. Scale bar, 20 μm.</p
Pituitary adenylate cyclase-activating polypeptide (PACAP) has been postulated to be involved in ... more Pituitary adenylate cyclase-activating polypeptide (PACAP) has been postulated to be involved in the development of psychiatric disorders. PACAP-deficient mice show behavioral and neurophysiological abnormalities including novelty-induced hyperlocomotion, emotional lability, depression-like behaviors, and memory impairments that are ameliorated with atypical antipsychotic drugs (serotonin–dopamine antagonists). Targeted deletion of the PACAP receptor PAC1 leads to several of these abnormalities. Genetic studies in humans suggest that single nucleotide polymorphisms and copy number variations of the PACAP and/or PACAP receptor genes may be a genetic risk factor for psychiatric disorders including schizophrenia. Although these findings in patients need further replication and the exact mechanisms for PACAP-dependent psychomotor regulation remain to be determined, several potential mechanisms have been proposed. Thus, the convergent evidence from animal models and humans suggest that PACAP signaling can be an intrinsic regulator of psychoneurological functions and an attractive therapeutic target for the disorders.
The present study examines the effect of the cognition enhancer (1R)-1benzo[b]thiophen-5-yl-2-[2-... more The present study examines the effect of the cognition enhancer (1R)-1benzo[b]thiophen-5-yl-2-[2-(diethylamino)ethoxy]ethan-1-ol hydrochloride (T-588) on neuronal injury induced by serum deprivation or amyloid-b protein (Ab). T-588 protected partially against neuronal injury induced by serum deprivation or Ab in cultured cortical neurons. T-588 did not affect the phosphorylation of extracellular signal-regulated kinase (ERK) in cortical neurons and SH-SY5Y cells. These results suggest that T-588 has a protective effect in neuronal injury models and the effect is not mediated by an ERK signal pathway.
The present study examined the effect of zotepine, an atypical antipsychotic, on the in vivo rele... more The present study examined the effect of zotepine, an atypical antipsychotic, on the in vivo release of monoamines in the prefrontal cortex of rats using microdialysis. Local perfusion of zotepine at 10 μM increased extracellular levels of serotonin (5-HT), as well as dopamine and noradrenaline, in the prefrontal cortex. However, systemic administration of zotepine did not affect 5-HT release, although it increased the dopamine and noradrenaline release. These results suggest that the prefrontal 5-HT system does not contribute to the antidepressant effect of zotepine. The difference in the effect of zotepine between local and systemic treatment is discussed.
Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is cha... more Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A nonstimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclaseactivating polypeptide (PACAP)-deficient (PACAP À/À) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP À/À mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP À/À mice compared to wildtype mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP À/À mice. Our current study suggests that PACAP À/ À mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP À/À mice on behaviors are discussed.
Metabotropic glutamate 2/3 receptor (mGluR2/3) agonists inhibit amphetamine-and phencyclidine-ind... more Metabotropic glutamate 2/3 receptor (mGluR2/3) agonists inhibit amphetamine-and phencyclidine-induced hyperactivity. Moreover, they ameliorate the deficits of attention and working memory induced by N-methyl-Daspartate (NMDA)-receptor antagonists. These findings suggest that activation of mGluR2/3 has a therapeutic potential for the treatment of schizophrenia (1). However, these models are not concerned with the environmental or developmental perspective in the etiology of schizophrenia. Rearing in social isolation from early life causes abnormal behaviors such as hyperactivity, aggressive behavior, deficits of prepulse inhibition (PPI), and cogni-tive impairments in rats and mice. Many of these behaviors strongly resemble core symptoms of schizophrenia (2). Moreover, anti-psychotic drugs such as risperidone and clozapine attenuate isolation rearing-induced aggressive behavior and PPI deficits in mice (3). We have recently shown that binding of the mGluR2/3 antagonist [ 3 H]LY341495 in the prefrontal cortex and hippocampus was increased by isolation rearing in mice (4). This suggests that dysfunction of the glutamatergic system including mGluR2/3 contributes to the mechanisms for isolation rearing-induced abnormal behaviors. To study the therapeutic potential of mGluR2/3 ligands for psychiatric disorders, this study examined the effect of MGS0028, a potent and selective mGluR2/3 agonist (5, 6), on the abnormal behaviors of isolation-reared mice. The experimental procedures concerning the use of
The behavior of isolation-reared mice has not yet been studied in the staircase test. The present... more The behavior of isolation-reared mice has not yet been studied in the staircase test. The present study examined the effects of anxiolytic or anxiogenic agents and isolation rearing on the behavior of ddY (outbred) strain mice in the staircase test. Diazepam and phenobarbital increased the number of steps climbed, but did not affect rearing behavior in group-reared mice. FG-7142, a benzodiazepine inverse agonist, significantly increased the number of rearing with no changes in the number of steps climbed in group-reared mice. Methamphetamine increased the number of steps climbed and decreased the number of rearing in group-reared mice. Although isolation-reared mice showed hyperactivity, there was no difference in locomotor activity for the test period of 3 min between isolation-and group-reared mice. Under these conditions, isolation rearing increased the numbers of steps climbed and rearing compared to group-reared controls. Microanalysis of locomotor patterns of group-reared mice in the staircase test showed that anxiolytic drugs increased the number of climbing to the top step of the staircase and methamphetamine increased the number of climbing to the first to third step. These results suggest that isolation rearing causes an anxiety-like state with increased exploratory behavior in mice.
Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induce... more Metabotropic glutamate (mGlu) 2/3 receptor agonists inhibit amphetamine- and phencyclidine-induced hyperlocomotion. The mechanism for the antipsychotic effect of mGlu2/3 receptor agonists was studied in a hypoglutamatergic model, but not a hyperdopaminergic model. To study the mechanism for the antipsychotic effect of the agonist in the hyperdopaminergic model, this study examined the effects of the selective mGlu2/3 receptor agonist MGS0028 on methamphetamine-induced hyperlocomotion and the increases in extracellular levels of serotonin, dopamine, noradrenaline, and glutamate in the prefrontal cortex and nucleus accumbens of mice. Systemic administration of MGS0028 attenuated methamphetamine-induced hyperlocomotion in a dose-dependent manner. Microdialysis studies showed that MGS0028 significantly inhibited methamphetamine-induced increases in the extracellular serotonin, but not dopamine and noradrenaline, levels in the prefrontal cortex, and it did not affect methamphetamine-induced increases in the extracellular amine levels in the nucleus accumbens. Methamphetamine did not affect the glutamate release in the prefrontal cortex and nucleus accumbens. Local application of MGS0028 into the prefrontal cortex also attenuated methamphetamine-induced hyperlocomotion and increases in the extracellular serotonin levels in the prefrontal cortex. Moreover, MGS0028 did not affect methamphetamine-induced hyperlocomotion in the mice pretreated with p-chlorophenylalanine, a serotonin synthesis inhibitor. Activation of prefrontal mGlu2/3 receptors inhibits the psychomotor stimulant effect of methamphetamine in mice, and the prefrontal serotonergic system may be involved in this effect. The finding provides evidence that prefrontal mGlu2/3 receptors are functionally coupled with the serotonergic system.
Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor act... more Chronic administration of methamphetamine (METH) elicits progressive enhancement of locomotor activity known as behavioral sensitization. We have recently shown that chronic METH enhanced METH challenge-induced increase in 5-HT levels in the prefrontal cortex and that 5-HT(1A) receptor activation attenuated this neurochemical sensitization as well as behavioral sensitization. This study examined whether the nonselective 5-HT(2) receptor antagonist, ritanserin affects METH-induced behavioral and neurochemical sensitization in mice. Ritanserin at doses of 1 and 3 mg/kg inhibited the development and expression of METH-induced behavioral sensitization in a dose-dependent manner. Furthermore, chronic administration of ritanserin for a week attenuated the maintenance of behavioral sensitization, indicating the improvement of established behavioral sensitization. Microdialysis analysis showed that chronic ritanserin inhibited the neurochemical sensitization that chronic METH enhanced METH challenge-induced increase in extracellular 5-HT levels in the prefrontal cortex. Furthermore, acute ritanserin inhibited METH challenge-induced increase in extracellular 5-HT but not DA levels in the prefrontal cortex. These results suggest that 5-HT(2) receptors are involved in METH-induced hyperactivity and behavioral sensitization in mice.
s / Neuroscience Research 68S (2010) e335–e446 e367 tions. Genetic tracing for DAergic lineage us... more s / Neuroscience Research 68S (2010) e335–e446 e367 tions. Genetic tracing for DAergic lineage using TH-Cre;Rosa26R-CFP mice revealed that the olfactory manipulations drastically altered the number of DAergic PGCs. Furthermore, we tested whether the positions that had lost PGCs were refilled with newly added PGCs. Interestingly, after the selective elimination of DAergic PGCs by in vivo two-photon laser ablation, same subtype of the PGCs was added into their positions. These observations suggest that the turnover dynamics of DAergic PGCs are dependent on the their spatio-temporal context and olfactory experience. doi:10.1016/j.neures.2010.07.1624 P3-e12 Injury-induced activation of cell proliferation and migration in the adult zebrafish telencephalon Norihito Kishimoto 1,2 , Kohei Shimizu 1, Kazunobu Sawamoto 1 1 Department of Dev and Regene Biol., Nagoya City University, Nagoya 2 Center for Integrated Medical Research, Keio University, Tokyo, Japan Recent studies have shown that adult neurogenesis is conserved in various vertebrates, including mammals, bird and reptiles. In the adult mammalian brain, newborn neurons in the subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) into the olfactory bulb (OB). On the other hand, they migrate toward injured area in injured brain. To provide new insights into the cellular and molecular mechanisms of adult neurogenesis, we have studied neuronal production and migration in zebrafish, in which powerful genetic approaches and in vivo imaging techniques are available. Our recent morphological studies have indicated that the adult fish brain possesses proliferating zone in the VZ and RMS-like route similar to those in rodents. Here, we provide direct evidence that neuronal progenitors migrate in the adult fish brain using a transgenic zebrafish line that expresses GFP under the control of the neuogenin1 promoter that is active in neuronal progenitor cells. In addition, we generated telencephalon injury in the adult zebrafish telencephalon. Lesion of adult zebrafish telencephalon stimulated cell proliferation in the VZ and the vicinity of the injured site, suggesting that the activation of the SVZ by brain injury is a common feature in vertebrates and that the adult zebrafish telecephalon injury is useful as a new model to investigate the molecular and cellular processes underlying neuronal regeneration. doi:10.1016/j.neures.2010.07.1625 P3-e13 Administration of NMDA receptor antagonist causes down-regulation of DISC1 expression and over migration of newly generated neurons in the adult hippocampus Takashi Namba 1,2 , Kotaro Hattori 3, Hiroshi Kunugi 3, Kozo Kaibuchi 1, Shigeo Uchino 2, Shinichi Kohsaka 2 1 Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Japan 2 Department of Neurochemistry, National Institute of Neuroscience, Tokyo, Japan 3 Department of Mental Disorder Research, National Institute of Neuroscience, Tokyo, Japan New neurons are continuously generated through out life in the hippocampus. Newly generated neurons migrate short distance and are integrated into pre-existing neuronal circuit. However, the extra cellular signals which regulate the neuronal migration are not fully understood. Here we report that NMDA receptor (NMDA-R) signaling is involved in cellular migration and proper positioning of newly generated neurons in the adult hippocampus. An intraperitoneal injection with an NMDA-R antagonist, memantine or CPP, into adult male mice caused aberrant positioning of Dcx-positive immature neurons. BrdU labeling analysis revealed that NMDA-R antagonist caused an over migration of newly generated neurons. Using a quantitative real-time PCR analysis, we examined the expression of Disrupted-In-Schizophrenia 1 (DISC1) that has been identified as a candidate susceptibility gene for major psychiatric disorders such as schizophrenia, because it has been known that DISC1 is one of the important molecules regulating migration of newly-generated neurons in the adult hippocampus. The expression of DISC1 in the dentate gyrus was reduced by NMDA-R antagonist-injection in a dose-dependent manner. In contrast, the expression of the DISC1interacting molecules, Lis1, NDEL1 and Girdin, was not affected by the NMDA-R antagonist-injection. These results suggest that the NMDA-R signaling affects the migration of newly generated neurons via regulating the expression of DISC1. doi:10.1016/j.neures.2010.07.1626 P3-e14 Investigating the roles of purinergic signaling in adult neurogenesis Satoshi Suyama , Takehiko Sunabori, Hideyuki Okano Department of Physiology, Keio University, School of Medicine, Japan It was long believed neurogenesis never occurs in the adult mammalian central nervous system (CNS). In the late 1990s, however, persistent neurogenesis was shown to occur in two restricted areas in adult mammalian brain: subventricular zone (SVZ) and subgranullar zone (SGZ) of the hippocampus. Within these neurogenic…
Biochemical and Biophysical Research Communications, Mar 1, 2015
Systematic and simultaneous analysis of multiple cell types in the brain is becoming important, b... more Systematic and simultaneous analysis of multiple cell types in the brain is becoming important, but such tools have not yet been adequately developed. Here, we aimed to generate a method for the specific fluorescent labeling of neurons and astrocytes, two major cell types in the brain, and we have developed lentiviral vectors to express the red fluorescent protein tdTomato in neurons and the enhanced green fluorescent protein (EGFP) in astrocytes. Importantly, both fluorescent proteins are fused to histone 2B protein (H2B) to confer nuclear localization to distinguish between single cells. We also constructed several expression constructs, including a tandem alignment of the neuron- and astrocyte-expression cassettes for simultaneous labeling. Introducing these vectors and constructs in vitro and in vivo resulted in cell type-specific and nuclear-localized fluorescence signals enabling easy detection and distinguishability of neurons and astrocytes. This tool is expected to be utilized for the simultaneous analysis of changes in neurons and astrocytes in healthy and diseased brains.
Mice lacking the PACAP gene (PACAP(-/-)) display psychomotor abnormalities such as novelty-induce... more Mice lacking the PACAP gene (PACAP(-/-)) display psychomotor abnormalities such as novelty-induced hyperactivity and jumping behavior, and they show different responses to amphetamine, a typical psychostimulant. The present study examined the possible role of endogenous PACAP in methamphetamine (METH)-induced hyperactivity and behavioral sensitization. The locomotor activity of hyperactive PACAP(-/-) mice was measured using the infrared photocell beam detection system, Acti-Track, after a habituation period. Single administration of METH (1 and 2mg/kg) caused a robust increase in locomotor activity of mice, but this effect did not differ between wild-type and PACAP(-/-) mice. Repeated administration of METH (1mg/kg) for 7 days enhanced METH-induced hyperactivity, and this sensitization was observed even when withdrawn for 7 days. There was no difference in the degree of development and expression of METH-induced behavioral sensitization between wild-type and PACAP(-/-) mice. In addition, there was no difference in METH-induced increases in extracellular serotonin and dopamine levels in the prefrontal cortex of the normal and sensitized mice between the two groups. These results suggest that endogenous PACAP is not involved in the locomotor stimulant activity of acute METH and repeated METH-induced behavioral and neurochemical sensitization.
This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluv... more This study examined the roles of presynaptic and postsynaptic serotonin type 1A receptors in fluvoxamine-induced inhibition of marble-burying behavior in mice. The effect of fluvoxamine was attenuated by the serotonin type 1A receptor antagonist WAY100635 at 1 mg/kg, while it was enhanced by the antagonist at 0.1 mg/kg. Fluvoxamine (30 mg/kg) and WAY100635 (0.1 and 1 mg/kg) did not affect spontaneous locomotor activity. These results suggest that the effect of fluvoxamine is mediated by postsynaptic serotonin type 1A receptors and it is enhanced by an inhibition of presynaptic serotonin type 1A receptors.
Pharmacology, Biochemistry and Behavior, Sep 1, 2006
Repeated intermittent administration of psychostimulants causes behavioral sensitization in roden... more Repeated intermittent administration of psychostimulants causes behavioral sensitization in rodents. Previous studies using serotonin (5-HT) receptor ligands show that the 5-HT system is involved in cocaine-induced behavioral sensitization in rats, but the role of the 5-HT system has not been studied in mice. The present study examined the effects of the 5-HT(1A) receptor agonist osemozotan, the 5-HT(2) receptor antagonist ritanserin and the 5-HT(3) receptor antagonist azasetron on cocaine-induced behavioral sensitization in male ddY mice. Repeated administration of cocaine for 7 days enhanced cocaine-induced locomotor activity, and this sensitization was observed even after withdrawal for 7-14 days. Cocaine-induced behavioral sensitization after a 7-day withdrawal was significantly reduced with the coadministration of osemozotan, ritanserin or azasetron with cocaine repeatedly for 7 days. A single injection of osemozotan or ritanserin before cocaine challenge also reduced repeated cocaine-induced behavioral sensitization. However, none of these ligands inhibited cocaine-induced behavioral sensitization, when each drug was administered for 7 days after repeated cocaine administration. These results suggest that the central 5-HT system plays a role in the development and expression, but not maintenance, of behavioral sensitization in cocaine-treated mice.
Previous studies suggest that metabotropic glutamate 2/3 receptors are involved in psychiatric di... more Previous studies suggest that metabotropic glutamate 2/3 receptors are involved in psychiatric disorders. In this study, we examined the effects of the selective metabotropic glutamate 2/3 (mGlu2/3) receptor agonist MGS0028 on behavioral abnormalities in mice lacking the pituitary adenylate cyclase-activating polypeptide (PACAP), an experimental model of psychiatric disorders such as schizophrenia and attention-deficit/hyperactivity disorder. We found that PACAP-deficient mice showed impairments in the novel object recognition test and these impairments were improved by MGS0028 (0.1 mg/kg). Similarly, MGS0028 improved hyperactivity and jumping behaviors, but did not reverse increased immobility times in the forced swim test in PACAP-deficient mice. These results suggest that MGS0028 may be a potential, novel treatment for psychiatric disorders.
Post-weaning social isolation in rodents induces behavioral alterations, including hyperlocomotio... more Post-weaning social isolation in rodents induces behavioral alterations, including hyperlocomotion, depression-and anxiety-like behaviors, aggression, and learning and memory deficits. These behavioral abnormalities may be related to the core symptoms in patients with neuropsychiatric disorders, such as schizophrenia and depression. In view of the recent studies that the group II metabotropic glutamate receptor (mGluR2/3) is involved in neuropsychiatric disorders, the present study examined the effect of isolation rearing on the binding of the mGluR2/3 antagonist [ 3 H]LY341495 to mGluR2/3 in the mouse brain by in vitro autoradiography. The [ 3 H]LY341495 binding in the prefrontal cortex, cerebral cortical layers IeIII and hippocampus was significantly increased by rearing in social isolation while the binding in other brain regions was not altered. A saturation binding study of hippocampal membranes from isolation-reared mice revealed that the B max value increased significantly without any changes in the K d value. Moreover, the mGluR2/3 antagonist MGS0039 (1.0 mg/kg, intraperitoneally) decreased the immobility time of isolation-reared mice in the forced swim test. These results suggest that isolation rearing causes an increase in mGluR2/3 densities in the prefrontal cortex and hippocampus and that the increased receptor function may contribute to pathogenic mechanisms for depression-like behavior of the isolation-reared mice.
The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive... more The effect of the benzodiazepine receptor antagonist flumazenil was examined on an antiaggressive effect of (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3- benzodioxole HCl (MKC-242), a 5-HT(1A) receptor agonist. MKC-242 (0.1-1.0 mg/kg, p.o.) selectively reduced isolation-induced aggressive behavior in a dose-dependent manner. Flumazenil (10 mg/kg, i.p.) antagonized the antiaggressive effects of MKC-242 and diazepam, although it alone did not affect the behaviors of isolated mice. These findings suggest that a gamma-aminobutyric acid(A) (GABA(A)) receptor system is involved in the antiaggressive effect by 5-HT(1A) receptor activation.
Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activi... more Repeated administration of psychostimulants elicits a progressive enhancement of locomotor activity known as behavioral sensitization. Central dopamine (DA) neurons play key roles as the neural substrates mediating behavioral sensitization, but the role of the serotonin (5-HT) system in the sensitization is not fully elucidated. We have recently demonstrated that osemozotan, a specific 5-HT 1A-receptor agonist, and ritanserin, a 5-HT 2-receptor antagonist, inhibited the expression and development of both methamphetamine-and cocaine-induced behavioral sensitization in mice and that these drugs attenuated the maintenance of behavioral sensitization of methamphetamine, but not that of cocaine. We also found that azasetron, a 5-HT 3-receptor antagonist, inhibited the expression and development of the sensitization induced by methamphetamine and cocaine, respectively. Neurochemical studies using a microdialysis technique showed that repeated methamphetamine enhanced the methamphetamine-induced increase in 5-HT release in the prefrontal cortex. The sensitization of 5-HT release in methamphetamine-treated mice was attenuated by osemozotan and ritanserin. These findings suggest that the 5-HT system plays an important role in methamphetamine-and cocaine-induced behavioral sensitization in mice and imply that 5-HT 1A-receptor agonists and 5-HT 2-receptor antagonists may have a potential therapeutic value for the treatment of methamphetamine abuse or psychosis.
Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activities includi... more Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts neurotrophic activities including modulation of synaptic plasticity and memory, hippocampal neurogenesis, and neuroprotection, most of which are shared with brain-derived neurotrophic factor (BDNF). Therefore, the aim of this study was to compare morphological effects of PACAP and BDNF on primary cultured hippocampal neurons. At days in vitro (DIV) 3, PACAP increased neurite length and number to similar levels by BDNF, but vasoactive intestinal polypeptide showed much lower effects. In addition, PACAP increased axon, but not dendrite, length, and soma size at DIV 3 similarly to BDNF. The PACAP antagonist PACAP6-38 completely blocked the PACAP-induced increase in axon, but not dendrite, length. Interestingly, the BDNF-induced increase in axon length was also inhibited by PACAP6-38, suggesting a mechanism involving PACAP signaling. K252a, a TrkB receptor inhibitor, inhibited axon outgrowth induced by PACAP and BDNF without affecting dendrite length. These results indicate that in primary cultured hippocampal neurons, PACAP shows morphological actions via its cognate receptor PAC 1 , stimulating neurite length and number, and soma size to a comparable extent as BDNF, and that the increase in total neurite length is ascribed to axon outgrowth.
Coadministration of atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) e... more Coadministration of atypical antipsychotics and selective serotonin reuptake inhibitors (SSRIs) enhances the release of monoamines such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the prefrontal cortex. To clarify the role of DAD 2/3 receptors in the combination effect, we examined the effects of coadministration of the selective DAD 2/3 antagonist sulpiride and the SSRI fluvoxamine on amine neurotransmitter release in rat prefrontal cortex. Sulpiride (10 mg/kg, i.p.) and fluvoxamine (10 mg/kg, i.p.) alone did not affect extracellular DA levels, while their coadministration caused a significant increase in DA levels. Sulpiride alone did not affect extracellular levels of 5-HT and NE in the prefrontal cortex, while fluvoxamine alone caused a marked increase in 5-HT levels and a slight increase in NE levels. Sulpiride did not affect the fluvoxamine-induced increases in extracellular levels of 5-HT and NE. The DAD 2/3 antagonist haloperidol (0.1 mg/kg) in combination with fluvoxamine also caused a selective increase in extracellular DA levels in the cortex. Coadministration of sulpiride and fluvoxamine did not affect extracellular DA levels in the striatum. Combination of systemic sulpiride and local fluvoxamine did not increase the DA levels, but that of systemic fluvoxamine with local sulpiride increased. The combination effect in increasing prefrontal DA levels was antagonized systemically, but not locally, by the 5-HT 1A antagonist WAY100635 at a low dose. These findings suggest that the combination of prefrontal DAD 2/3 receptor blockade and 5-HT 1A receptor activation in regions other than the cortex plays an important role in sulpiride and fluvoxamine-induced increase in prefrontal DA release.
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