Saki Shimizu

Osaka University of Pharmaceutical Sciences, Takatuki, Ōsaka, Japan

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Publications (22)51.86 Total impact

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    ABSTRACT: .Background: The inwardly rectifying potassium channel subunit Kir4.1 is specifically expressed in astrocytes, which mediates spatial K+ buffering and is implicated in the pathogenesis of convulsive epileptic disorders (i.e. generalized tonic-clonic (GTC) and temporal lobe seizures). Objectives: This study aimed to explore the pathophysiological role of Kir4.1 channels in modulating absence seizure incidence, using a spontaneously epileptic animal model. Materials and Methods: Groggy rats, a rat model of human absence seizures, and Slc:Wistar (control) rats, were used in this study. Cortical and hippocampal EEG were recorded to confirm the seizure incidence in Groggy rats. The expression levels of Kir subunits (i.e. Kir4.1, Kir5.1 and Kir2.1) in ten brain regions were analyzed by Western blotting. Results: Groggy rats showed a high incidence (ca. 350 seconds total duration/15 minutes observation period) of absence-like seizures, which were characterized by a sudden immobile posture and synchronously-associated spike and wave discharges. However, Western blot analysis revealed that Kir4.1 expression in Groggy rats was not significantly different from that of control rats in any of the brain regions examined (e.g. cerebral cortex, striatum, hippocampus, diencephalon, midbrain, pons/medulla oblongata and cerebellum). In addition, expressional levels of Kir5.1 and Kir2.1, which are also expressed in astrocytes, were unaltered in Groggy rats. Conclusions: The present results suggest that unlike GTC and temporal lobe seizures, pathophysiological alterations (e.g. dysfunction and/or expressional changes) of Kir4.1 are not linked to non-convulsive absence seizures.
    Archiv Neurosci. 01/2014; 2(1):e18651.
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    ABSTRACT: Dopamine D3 receptors are highly expressed in the cerebellum; however, their pathophysiological functions are not fully understood. Here, we conducted microinjection studies to clarify the role of cerebellar D3 receptors in modulating locomotion and cataleptogenicity in rats. Microinjection of the preferential D3 agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) into lobe 9 of the cerebellum significantly reduced spontaneous locomotor activity with a U-shaped dose-response curve. The intracerebellar microinjection of 7-OH-DPAT did not elicit catalepsy by itself, but markedly potentiated catalepsy induction with a low dose (0.3mg/kg) of haloperidol. The catalepsy enhancement by 7-OH-DPAT occurred in a dose-dependent manner and was not associated with the locomotor inhibition. U-99194A (a selective D3 antagonist) or AD-6048 (a preferential D3 vs. D2 antagonist) antagonized both the catalepsy enhancement and the locomotor inhibition with 7-OH-DPAT. In addition, U-99194A and AD-6048 per se significantly alleviated catalepsy induced by a high dose (0.5mg/kg) of haloperidol. Furthermore, microinjection of 7-OH-DPAT into the nucleus accumbens or the dorsolateral striatum neither affected spontaneous locomotor activity nor haloperidol (0.3mg/kg)-induced catalepsy. The present results illustrate for the first time the role of cerebellar D3 receptors in modulating cataleptogenicity of antipsychotic, implying that blockade of cerebellar D3 receptors contributes to the reduction of extrapyramidal side effects.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 12/2013; · 3.55 Impact Factor
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    ABSTRACT: Sleep apnea (SA) causes not only sleep disturbances, but also neurocognitive impairments and/or psychoemotional disorders. Here, we studied the effects of intermittent hypoxia (IH) on forebrain Fos expression using obese diabetic db/db mice to explore the pathophysiological alterations in neural activities and the brain regions related to SA syndrome. Male db/db mice were exposed to IH stimuli (repetitive 6-min cycles of 1min with 5% oxygen followed by 5min with 21% oxygen) for 8hours (80 cycles) per day or normoxic condition (control group) for 14 days. Fos protein expression was immunohistochemically examined a day after the last IH exposure. Mapping analysis revealed a significant reduction of Fos expression by IH in limbic and paralimbic structures, including the cingulate and piriform cortices, the core part of the nucleus accumbens and most parts of the amygdala (i.e., the basolateral and basomedial amygdaloid nuclei, cortical amygdaloid area and medial amygdaloid nucleus). In the brain stem regions, Fos expression was region-specifically reduced in the ventral tegmental area while other regions including the striatum, thalamus and hypothalamus, were relatively resistant against IH. In addition, db/db mice exposed to IH showed a trend of sedative and/or depressive behavioral signs in the open field and forced swim tests. The present results illustrate that SA in the obese diabetic model causes neural suppression preferentially in the limbic and paralimbic regions, which may be related to the neuropsychological disturbances associated with SA.
    Neuroscience Research 10/2013; · 2.20 Impact Factor
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    ABSTRACT: We previously demonstrated that 5-HT stimulants, including selective serotonin reuptake inhibitors (SSRIs), potentiated antipsychotic-induced extrapyramidal symptoms (EPS) by stimulating 5-HT2A/2C, 5-HT3 and 5-HT6 receptors. Here, we studied the effects of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin ((±)-8-OH-DPAT) on the fluoxetine enhancement of EPS (i.e., bradykinesia and catalepsy) to determine if the 5-HT1A agonist can counteract the serotonergic potentiation of EPS. Fluoxetine did not induce EPS signs by itself, but significantly potentiated haloperidol-induced bradykinesia in mice. (±)-8-OH-DPAT (0.1-1 mg/kg, i.p.) significantly attenuated the fluoxetine enhancement of haloperidol-induced bradykinesia in a dose-dependent manner. A selective 5-HT1A antagonist (s)-WAY-100135 completely reversed the anti-EPS action of (±)-8-OH-DPAT. Microinjection studies using rats revealed that local application of (±)-8-OH-DPAT into the dorsolateral striatum or the motor cortex significantly diminished fluoxetine-enhanced catalepsy. In contrast, (±)-8-OH-DPAT injected into the medial raphe nucleus failed to affect EPS induction. The present results illustrate that 5-HT1A agonist can alleviate the SSRI enhancement of EPS by activating postsynaptic 5-HT1A receptors in the striatum and cerebral cortex.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2013; · 3.55 Impact Factor
  • Saki Shimizu, Yukihiro ohno
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    ABSTRACT: The serotonergic system plays a crucial role in regulating psychoemotional, sensorimotor and cognitive functions in the central nervous system. Among 5-HT receptor subtypes, 5-HT1A receptors are implicated in the pathogenesis and treatment of anxiety and depression. In addition, recent research into 5-HT1A receptors has revealed new therapeutic roles in the treatment of Parkinson’s disease. Specifically, 5-HT1A receptors modulate extrapyramidal motor disorders, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and cognitive impairments. Thus, full or partial 5-HT1A agonists improve core parkinsonian symptoms associated with dopaminergic deficits, dyskinesia induced by chronic L-DOPA treatment and mood disturbances (anxiety and depression). In addition, partial 5-HT1A agonists or antagonists are expected to be effective against cognitive impairments in patients with Parkinson’s disease. These findings encourage the discovery of new 5-HT1A receptor ligands, which may improve limitations in efficacy and/or adverse reactions in the current therapy of Parkinson’s disease.
    07/2013: pages 306-324; , ISBN: 978-1-84973-617-6
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    ABSTRACT: The inwardly rectifying potassium channel subunit Kir4.1 is expressed in brain astrocytes and involved in spatial K(+) buffering, regulating neural activity. To explore the pathophysiological alterations of Kir4.1 channels in epileptic disorders, we analyzed interictal expressional levels of Kir4.1 in the Noda epileptic rat (NER), a hereditary animal model for generalized tonic-clonic (GTC) seizures. Western blot analysis showed that Kir4.1 expression in NERs was significantly reduced in the occipito-temporal cortical region and thalamus. However, the expression of Kir5.1, another Kir subunit mediating spatial K(+) buffering, remained unaltered in any brain regions examined. Immunohistochemical analysis revealed that Kir4.1 was primarily expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes (somata) and foot processes clustered around neurons proved with anti-neuronal nuclear antigen (NeuN) antibody. In NERs, Kir4.1 expression in astrocytic processes was region-selectively diminished in the amygdaloid nuclei (i.e., medial amygdaloid nucleus and basomedial amygdaloid nucleus) while Kir4.1 expression in astrocytic somata was unchanged. Furthermore, the amygdala regions with reduced Kir4.1 expression showed a marked elevation of Fos protein expression following GTC seizures. The present results suggest that reduced activity of astrocytic Kir4.1 channels in the amygdala is involved in limbic hyperexcitability in NERs.
    Brain research 04/2013; · 2.46 Impact Factor
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    Saki Shimizu, Yukihiro Ohno
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    ABSTRACT: Parkinson's disease, the most common neurological disorder in the elderly, is characterized by progressive extrapyramidal motor dysfunction including resting tremors, muscle rigidity, hypolocomotion (bradykinesia and akinesia) and postural instability. Various non-motor features are also seen such as cognitive impairments (deficits in learning and memory) and mood disorders (depression and anxiety). While the 5-HT(1A) receptor has long been implicated in the pathogenesis and treatment of anxiety and depression, recent research has revealed new therapeutic roles for 5-HT(1A) receptors in the treatment of Parkinson's disease. These include the modulation of parkinsonian motor symptoms, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, cognitive impairments and emesis. Thus, 5-HT(1A) agonists improve the various motor disorders associated with dopaminergic deficits, dyskinesia induced by chronic L-DOPA treatment, mood disturbances (anxiety and depression) and dopamine agonist-induced emesis. In addition, partial 5-HT(1A) agonists are expected to improve cognitive impairment in Parkinson's patients. These findings encourage research into new 5-HT(1A) receptor ligands, which will improve efficacy and/or ameliorate adverse reactions in the treatment of Parkinson's disease.
    Aging and disease. 02/2013; 4(1):1-13.
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    ABSTRACT: The inwardly rectifying potassium (Kir) channel Kir4.1 in brain astrocytes mediates spatial K(+) buffering and regulates neural activities. Recent studies have shown that loss-of-function mutations in the human gene KCNJ10 encoding Kir4.1 cause epileptic seizures, suggesting a close relationship between the Kir4.1 channel function and epileptogenesis. Here, we performed expressional analysis of Kir4.1 in a pilocarpine-induced rat model of temporal lobe epilepsy (TLE) to explore the role of Kir4.1 channels in modifying TLE epileptogenesis. Treatment of rats with pilocarpine (350 mg/kg, i.p.) induced acute status epilepticus, which subsequently caused spontaneous seizures 7-8 weeks after the pilocarpine treatment. Western blot analysis revealed that TLE rats (interictal condition) showed significantly higher levels of Kir4.1 than the control animals in the cerebral cortex, striatum, and hypothalamus. However, the expression of other Kir subunits, Kir5.1 and Kir2.1, remained unaltered. Immunohistochemical analysis illustrated that Kir4.1-immunoreactivity-positive astrocytes in the pilocarpine-induced TLE model were markedly increased in most of the brain regions examined, concomitant with an increase in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. In addition, Kir4.1 expression ratios relative to the number of astrocytes (Kir4.1-positive cells/GFAP-positive cells) were region-specifically elevated in the amygdala (i.e., medial and cortical amygdaloid nuclei) and sensory cortex. The present study demonstrated for the first time that the expression of astrocytic Kir4.1 channels was elevated in a pilocarpine-induced TLE model, especially in the amygdala, suggesting that astrocytic Kir4.1 channels play a role in modifying TLE epileptogenesis, possibly by acting as an inhibitory compensatory mechanism.
    Frontiers in Cellular Neuroscience 01/2013; 7:104. · 4.47 Impact Factor
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    ABSTRACT: Antipsychotic-induced extrapyramidal motor disorders such as parkinsonian symptoms (e.g., bradykinesia, tremor and muscle rigidity), akathisia, dystonia and tardive dyskinesia are the most common neurological side effects in the treatment of schizophrenia. It is now known that the serotonergic nervous system modulates the induction of antipsychotic-induced extrapyramidal side effects (EPS) via diverse mechanisms mediated by multiple 5-HT receptors. Antagonism of 5-HT2A/2C receptors has been shown to alleviate antipsychotic-induced EPS by relieving the 5-HT2A/2C receptor-mediated inhibition of nigro-striatal dopaminergic neurons. Many of the second-generation antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, perospirone, ziprasidone, blonanserin and lurasidone) possess potent 5-HT2A/2C blocking activity, which contributes to their atypical antipsychotic properties. In addition, 5-HT1A receptors also play an important role in modulating EPS induction. Microinjection studies revealed that stimulation of postsynaptic 5-HT1A receptors in the striatum or cerebral cortex, as well as presynaptic 5-HT1A autoreceptors in the raphe nuclei, attenuates antipsychotic-induced EPS. Indeed, several atypical antipsychotics (e.g., perospirone, ziprasidone, aripiprazole and lurasidone) show a high affinity to 5-HT1A receptors. Furthermore, recent studies demonstrated that antagonism of 5-HT3 and 5-HT6 receptors alleviates antipsychotic-induced EPS. In this chapter, the functional roles and mechanisms of 5-HT receptors in modulating antipsychotic-induced EPS are reviewed.
    01/2013: pages 219-234; , ISBN: 978-1-62257-459-9
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    ABSTRACT: The serotonergic nervous system plays crucial roles in regulating psycho-emotional, cognitive, sensori-motor and autonomic functions. It is now known that multiple serotonin (5-hydroxytryptamine; 5-HT) receptors regulate extrapyramidal motor functions, which are implicated in pathogenesis and/or treatment of various neurological disorders (e.g., Parkinson's disease and drug-induced extrapyramidal motor deficits). Specifically, antagonism of 5-HT2A/2C receptors alleviates antipsychotic-induced extrapyramidal side effects (EPS) by relieving the 5-HT2A/2C receptor-mediated inhibition of nigral dopaminergic neuron activity and striatal dopamine release. Indeed, many of the second generation antipsychotics (e.g., risperidone, perospirone and olanzapine) commonly possess potent 5-HT2A/2C blocking actions which contribute to their atypical antipsychotic property. In addition, activation of 5-HT1A receptors also improves antipsychotic-induced EPS and motor disabilities in animal models of Parkinson's disease. Microinjection studies revealed that stimulation of postsynaptic 5-HT1A receptors in the striatum or motor cortex plays an important role in the antiparkinsonian actions. Furthermore, recent studies demonstrated that antagonism of 5-HT3 and 5-HT6 receptors alleviates extrapyramidal motor disorders while 5-HT4, 5-HT5, and 5-HT7 receptors are mostly inactive. These results encourage drug discovery research into new 5-HT receptor ligands that could improve current therapies for extrapyramidal motor disorders.
    Biological & Pharmaceutical Bulletin 01/2013; 36(9):1396-400. · 1.85 Impact Factor
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    ABSTRACT: Patients with schizophrenia exhibit diverse psychotic symptoms including positive symptoms (e.g., hallucinations and delusions), negative symptoms (e.g., apathy and emotional withdrawal) and cognitive impairments (e.g., inattention, deficits in social recognition, learning and memory). Although newly-developed atypical antipsychotic drugs (e.g., risperidone, olanzapine, quetiapine, perospirone and aripiprazole) provide benefits in the treatment of schizophrenia, clinical reports do not show significant advantages of the above 2nd generation antipsychotics beyond typical ones (e.g., haloperidol), especially in their efficacy against neurocognitive impairments. Recently, several lines of studies revealed the therapeutic role of 5-HT receptors in treating cognitive impairments in schizophrenia and other disorders (e.g., Alzheimer's disease). Specifically, inhibition of 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT4 receptors seem to be promising strategies for alleviating cognitive impairments. In this chapter, the therapeutic role and functional mechanisms of 5-HT receptors in modulating cognitive deficits in schizophrenia are reviewed.
    07/2012: pages 323-338; , ISBN: 978-1-61942-459-3
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    ABSTRACT: Spontaneously hypertensive rats (SHR) are widely used as a rat model of attention deficit/hyperactivity disorder (AD/HD). Here, we conducted neurochemical and behavioral studies in SHR to clarify the topographical alterations in neurotransmissions linked to their behavioral abnormalities. In the open-field test, juvenile SHR showed a significant hyperactivity in ambulation and rearing as compared with Wistar Kyoto rats (WKY). Brain mapping analysis of Fos-immunoreactivity (IR) revealed that SHR showed a marked increase in Fos expression in the core part (AcC) of the nucleus accumbens (NAc). Small to moderate increases were also observed in the shell part of the NAc and some regions of the cerebral cortex (e.g., parietal association cortex). These changes in Fos expression were region-specific and the Fos-IR levels in other brain regions (e.g., hippocampus, amygdala, striatum, thalamus and hypothalamus) were unaltered. In addition, treatment of SHR with the selective D(1) antagonist SCH-23390 significantly reversed both behavioral hyperactivity and elevated Fos expression in the AcC and cerebral cortex. The present study suggests that D(1) receptor-mediated neurotransmission in the AcC is region-specifically elevated in SHR, which could be responsible for behavioral hyperactivity.
    Neuropharmacology 05/2012; 63(4):547-54. · 4.11 Impact Factor
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    ABSTRACT: Antipsychotic drugs are widely used not only for schizophrenia, but also for mood disorders such as bipolar disorder and depression. To evaluate the interactions between antipsychotics and drugs for mood disorders in modulating extrapyramidal side effects (EPS), we examined the effects of antidepressants and mood-stabilizing drugs on haloperidol (HAL)-induced bradykinesia and catalepsy in mice and rats. The selective serotonin reuptake inhibitors (SSRIs), fluoxetine and paroxetine, and the tricyclic antidepressant (TCA) clomipramine, which showed no EPS by themselves, significantly potentiated HAL-induced bradykinesia and catalepsy in a dose-dependent manner. In contrast, the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine failed to augment, but rather attenuated HAL-induced bradykinesia and catalepsy. Mianserin also tended to reduce the EPS induction. In addition, neither treatment with lithium, sodium valproate nor carbamazepine potentiated HAL-induced EPS. Furthermore, treatment of animals with ritanserin (5-HT2A/2C antagonist), ondansetron (5-HT3 antagonist), and SB-258585 (5-HT6 antagonist) significantly antagonized the EPS augmentation by fluoxetine. Intrastriatal injection of ritanserin or SB-258585, but not ondansetron, also attenuated the EPS induction. The present study suggests that NaSSAs are superior to SSRIs or TCAs in combined therapy for mood disorders with antipsychotics in terms of EPS induction. In addition, 5-HT2A/2C, 5-HT3 and 5-HT6 receptors seem to be responsible for the augmentation of antipsychotic-induced EPS by serotonin reuptake inhibitors.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 04/2012; 38(2):252-9. · 3.55 Impact Factor
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    ABSTRACT: Mutations of the voltage-gated sodium (Na(v)) channel subunit SCN1A have been implicated in the pathogenesis of human febrile seizures including generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI). Hyperthermia-induced seizure-susceptible (Hiss) rats are the novel rat model carrying a missense mutation (N1417H) of Scn1a, which is located in the third pore-forming region of the Na(v)1.1 channel. Here, we conducted behavioral and neurochemical studies to clarify the functional relevance of the Scn1a mutation in vivo and the mechanism underlying the vulnerability to hyperthermic seizures. Hiss rats showed markedly high susceptibility to hyperthermic seizures (mainly generalized clonic seizures) which were synchronously associated with paroxysmal epileptiform discharges. Immunohistochemical analysis of brain Fos expression revealed that hyperthermic seizures induced a widespread elevation of Fos-immunoreactivity in the cerebral cortices including the motor area, piriform, and insular cortex. In the subcortical regions, hyperthermic seizures enhanced Fos expression region--specifically in the limbic and paralimbic regions (e.g., hippocampus, amygdala, and perirhinal-entorhinal cortex) without affecting other brain regions (e.g., basal ganglia, diencephalon, and lower brainstem), suggesting a primary involvement of limbic system in the induction of hyperthermic seizures. In addition, Hiss rats showed a significantly lower threshold than the control animals in inducing epileptiform discharges in response to local stimulation of the hippocampus (hippocampal afterdischarges). Furthermore, hyperthermic seizures in Hiss rats were significantly alleviated by the antiepileptic drugs, diazepam and sodium valproate, while phenytoin or ethosuximide were ineffective. The present findings support the notion that Hiss rats are useful as a novel rat model of febrile seizures and suggest that hyperexcitability of limbic neurons associated with Scn1a missense mutation plays a crucial role in the pathogenesis of febrile seizures.
    Neurobiology of Disease 09/2010; 41(2):261-9. · 5.62 Impact Factor
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    ABSTRACT: Previous studies have revealed that 5-HT(1A) agonists ameliorate antipsychotic-induced extrapyramidal symptoms (EPS) through postsynaptic 5-HT(1A) receptors. Here, we conducted an intracerebral microinjection study of (+/-)-8-hydroxy-2-(di-n-propylamino)-tetralin ((+/-)8-OH-DPAT) to determine the action site of the 5-HT(1A) agonist in alleviating EPS. Bilateral microinjection of(+/-)8-OH-DPAT (5 microg/1microL per side) either into the primary motor cortex (MC) or the dorsolateral striatum (dlST) significantly attenuated haloperidol-induced catalepsy in rats. The anticataleptic action of (+/-)8-OH-DPAT was more prominent with the MC injection than with the dlST injection. WAY-100135 (a selective 5-HT(1A) antagonist) completely antagonized the reversal of haloperidol-induced catalepsy both by intracortical and intrastriatal (+/-)8-OH-DPAT. Furthermore, lesioning of dopamine neurons with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg/day, i.p., for 4 days) did not alter the anti-EPS actions of (+/-)8-OH-DPAT in a mouse pole test. The present results strongly suggest that 5-HT(1A) agonist alleviates antipsychotic-induced EPS by activating postsynaptic 5-HT(1A) receptors in the MC and dlST, probably through non-dopaminergic mechanisms.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2010; 34(6):877-81. · 3.55 Impact Factor
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    ABSTRACT: Blonanserin is a novel antipsychotic agent that preferentially interacts with dopamine D(2) and 5-HT(2A) receptors. To assess the atypical properties of blonanserin, we evaluated its propensity to induce extrapyramidal side effects (EPS) and to enhance forebrain Fos expression in mice. The actions of AD-6048, a primary metabolite of blonanserin, in modulating haloperidol-induced EPS were also examined. Blonanserin (0.3-10mg/kg, p.o.) did not significantly alter the pole-descending behavior of mice in the pole test or increase the catalepsy time, while haloperidol (0.3-3mg/kg, p.o.) caused pronounced bradykinesia and catalepsy. Blonanserin and haloperidol at the above doses significantly enhanced Fos expression in the shell (AcS) region of the nucleus accumbens and dorsolateral striatum (dlST). The extent of blonanserin-induced Fos expression in the AcS was comparable to that induced by haloperidol. However, the striatal Fos expression by blonanserin was less prominent as compared to haloperidol. Furthermore, combined treatment of AD-6048 (0.1-3mg/kg, s.c.) with haloperidol (0.5mg/kg, i.p.) significantly attenuated haloperidol-induced bradykinesia and catalepsy. The present results show that blonanserin behaves as an atypical antipsychotic both in inducing EPS and enhancing forebrain Fos expression. In addition, AD-6048 seems to contribute at least partly to the atypical properties of blonanserin.
    Pharmacology Biochemistry and Behavior 08/2010; 96(2):175-80. · 2.61 Impact Factor
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    ABSTRACT: Noda epileptic rat (NER) is a genetic rat model of epilepsy that exhibit spontaneous generalized tonic-clonic (GTC) seizures with paroxysmal discharges. We analyzed the regional expression of Fos-like immunoreactivity (Fos-IR) following GTC seizures in NER to clarify the brain regions involved in the seizure generation. GTC seizures in NER elicited a marked increase in Fos expression in the piriform cortex, perirhinal-entorhinal cortex, insular cortex and other cortices including the motor cortex. In the limbic regions, Fos-IR was highest in the amygdalar nuclei (e.g., basomedial amygdaloid nucleus), followed by the cingulate cortex and hippocampus (i.e., dentate gyrus and CA3). As compared to the above forebrain regions, NER either with or without GTC seizures exhibited only marginal Fos expression in the basal ganglia (e.g., accumbens, striatum and globus pallidus), diencephalon (e.g., thalamus and hypothalamus) and lower brain stem structures (e.g., pons-medulla oblongata). These results suggest that GTC seizures in NER are of forebrain origin and are evoked primarily by activation of the limbic and/or cortical seizure circuits.
    Epilepsy research 09/2009; 87(1):70-6. · 2.48 Impact Factor
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    Yukihiro Ohno, Saki Shimizu, Junta Imaki
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    ABSTRACT: We studied the effects of tandospirone, a 5-HT(1A) agonistic anxiolytic agent, on haloperidol-induced catalepsy and forebrain Fos expression in mice. Haloperidol (0.5 mg/kg, i.p.) markedly increased the catalepsy time and enhanced Fos expression in the shell (AcS) and core (AcC) regions of the nucleus accumbens, the dorsolateral striatum (dlST), and the lateral septal nucleus (LSN). Tandospirone (0.1 - 1 mg/kg, s.c.) significantly alleviated haloperidol-induced catalepsy in a dose-dependent manner, which was antagonized by WAY-100135 (a selective 5-HT(1A) antagonist). The anticataleptic dose of tandospirone (1 mg/kg, s.c.) significantly reduced haloperidol-induced Fos expression in the dlST. This inhibition by tandospirone was regionally specific, and it failed to affect haloperidol-induced Fos expression either in the AcS, AcC, or LSN. In addition, the reversal of haloperidol-induced striatal Fos expression by tandospirone was antagonized by WAY-100135. These results support the notion that stimulation of 5-HT(1A) receptors region-specifically counteracts the D(2)-blocking actions of haloperidol in the striatum, which may account for the ameliorative effects of 5-HT(1A) agonists on antipsychotic-associated extrapyramidal disorders.
    Journal of Pharmacological Sciences 05/2009; 109(4):593-9. · 2.15 Impact Factor
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    ABSTRACT: We examined the effects of JP-1302 (a selective alpha2C antagonist), BRL-44408 (a selective alpha2A antagonist) and yohimbine (a non-selective alpha2 antagonist) on haloperidol-induced bradykinesia and catalepsy in mice to elucidate the role of alpha2 adrenoceptor subtypes in modifying extrapyramidal motor disorders. JP-1302 (0.1-1 mg/kg, s.c.) dose-dependently ameliorated haloperidol-induced bradykinesia in the pole-test and reversed the catalepsy time increased by haloperidol. Antibradykinetic and anticataleptic actions of JP-1302 were statistically significant at 0.3 and 1 mg/kg, and these doses did not alter the ambulatory distance, rearing or center-perimeter residence time in the open-field test. BRL-44408 (1-10 mg/kg, s.c.) and yohimbine (0.3-3 mg/kg, i.p.) also ameliorated haloperidol-induced bradykinesia and catalepsy. However, both agents significantly decreased ambulatory distance and rearing in the open-field test, possibly reflecting their anxiogenic actions associated with alpha2A antagonism. The present study shows for the first time that blockade of alpha2C receptors can alleviate antipsychotic-induced extrapyramidal motor disorders without affecting gross behaviors.
    Neuroscience Letters 05/2009; 454(2):143-7. · 2.03 Impact Factor
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    ABSTRACT: To clarify the role and mechanism of the 5-HT1A receptor in modulating extrapyramidal motor disorders, we studied the actions of 5-HT1A agonists in the mouse pole test, a valid model of parkinsonian bradykinesia. Haloperidol markedly delayed pole-descending behavior of mice in the pole test, and this effect was alleviated by the antiparkinsonian agent trihexyphenidyl (a muscarinic antagonist). The selective 5-HT1A agonists, 8-hydroxydipropylaminotetraline (8-OH-DPAT) and tandospirone, significantly attenuated haloperidol-induced bradykinesia in a dose-dependent manner. The alleviation of haloperidol-induced bradykinesia by 8-OH-DPAT was completely antagonized by WAY-100135 (a selective 5-HT1A antagonist), but was unaffected by cerebral 5-HT depletion with p-chlorophenylalanine (PCPA) treatment (300 mg/kg, i.p. for 3 days). These results suggest that 5-HT1A agonists improve extrapyramidal motor disorders associated with antipsychotic treatments by stimulating the postsynaptic 5-HT1A receptor.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 08/2008; 32(5):1302-7. · 3.55 Impact Factor