Saki Shimizu

Osaka University of Pharmaceutical Sciences, Takatuki, Ōsaka, Japan

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Publications (29)77.88 Total impact

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    ABSTRACT: Parkinson's disease (PD) is a common, late-onset neurodegenerative disorder that shows progressive extrapyramidal motor disorders (e.g., bradykinesia, resting tremors, muscle rigidity and postural instability) and various non-motor symptoms (e.g., cognitive impairment, mood disorders, autonomic dysfunction and sleep disorders). While dopaminergic agents such as L-3,4-dihydroxyphenylalanine (L-DOPA) and dopamine D2 agonists are widely used for the treatment of PD, there is still high clinical unmet need for novel medications that overcome the limitations of current therapies. Evidence is now accumulating that the serotonergic nervous system is involved in the pathophysiological basis of PD and can provide benefits in the treatment of PD through its diverse functions. Among 5-HT receptor subtypes, 5-HT1A, 5-HT2, 5-HT3 and 5-HT6 receptors play an important role in modulating extrapyramidal motor disorders. In addition, 5-HT1A, 5-HT2, 5-HT3, 5-HT4 and 5-HT6 receptors are implicated in modulation of cognitive impairment, mood disorders (e.g., depression and anxiety) and/or psychosis, which are frequently observed in patients with PD. Specifically, stimulation of 5-HT1A receptors seems to be effective for multiple PD symptoms including parkisonism, L-DOPA-induced dyskinesia, cognitive impairment, mood disorders and neurodegeneration of dopamine neurons. Blockade of 5-HT2 receptors is also likely to improve parkinsonism, depressive mood and cognitive impairment. In addition, it was recently demonstrated that 5-HT2A inverse agonists can alleviate PD psychosis. All these findings emphasize the therapeutic roles of the serotonergic system in PD and stimulate new insight into novel treatments by modulating 5-HT1A and 5-HT2 receptors.
    Full-text · Article · Nov 2015 · Progress in Neurobiology
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    ABSTRACT: Blonanserin is a new atypical antipsychotic drug that shows high affinities to dopamine D2 and 5-HT2 receptors; however, the mechanisms underlying its atypicality are not fully understood. In this study, we evaluated the antipsychotic properties of AD-6048, a primary metabolite of blonanserin, to determine if it contributes to the atypicality of blonanserin. Subcutaneous administration of AD-6048 (0.3-1mg/kg) significantly inhibited apomorphine (APO)-induced climbing behavior with an ED50 value of 0.200mg/kg, the potency being 1/3-1/5 times that of haloperidol (HAL). AD-6048 did not cause extrapyramidal side effects (EPS) even at high doses (up to 10mg/kg, s.c.), whereas HAL at doses of 0.1-3mg/kg (s.c.) significantly induced bradykinesia and catalepsy in a dose-dependent manner. Thus, the therapeutic index (potency ratios of anti-APO action to that of EPS induction) of AD-6048 was much higher than that of haloperidol, illustrating that AD-6048 per se possesses atypical antipsychotic properties. In addition, immunohistochemical analysis of Fos protein expression revealed that both AD-6048 and HAL significantly increased Fos expression in the shell part of the nucleus accumbens and the striatum. However, in contrast to HAL which preferentially enhanced striatal Fos expression, AD-6048 showed a preferential action to the nucleus accumbens. These results indicate that AD-6048 acts as an atypical antipsychotic, which seems to at least partly contribute to the atypicality of blonanserin.
    Full-text · Article · Sep 2015 · Pharmacology Biochemistry and Behavior
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    ABSTRACT: Genetic factors are thought to play a major role in the etiology of essential tremor (ET); however, few genetic changes that induce ET have been identified to date. In the present study, to find genes responsible for the development of ET, we employed a rat model system consisting of a tremulous mutant strain, TRM/Kyo (TRM), and its substrain TRMR/Kyo (TRMR). The TRM rat is homozygous for the tremor (tm) mutation and shows spontaneous tremors resembling human ET. The TRMR rat also carries a homozygous tm mutation but shows no tremor, leading us to hypothesize that TRM rats carry one or more genes implicated in the development of ET in addition to the tm mutation. We used a positional cloning approach and found a missense mutation (c. 1061 C>T, p. A354V) in the hyperpolarization-activated cyclic nucleotide-gated 1 channel (Hcn1) gene. The A354V HCN1 failed to conduct hyperpolarization-activated currents in vitro, implicating it as a loss-of-function mutation. Blocking HCN1 channels with ZD7288 in vivo evoked kinetic tremors in nontremulous TRMR rats. We also found neuronal activation of the inferior olive (IO) in both ZD7288-treated TRMR and non-treated TRM rats and a reduced incidence of tremor in the IO-lesioned TRM rats, suggesting a critical role of the IO in tremorgenesis. A rat strain carrying the A354V mutation alone on a genetic background identical to that of the TRM rats showed no tremor. Together, these data indicate that body tremors emerge when the two mutant loci, tm and Hcn1A354V, are combined in a rat model of ET. In this model, HCN1 channels play an important role in the tremorgenesis of ET. We propose that oligogenic, most probably digenic, inheritance is responsible for the genetic heterogeneity of ET.
    Full-text · Article · May 2015 · PLoS ONE
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    ABSTRACT: Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD). Here, we examined the effects of cholinesterase inhibitors (ChEIs), donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS) in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3-3 mg/kg) did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg) in dose-dependent and synergistic manners. Galantamine (0.3-3 mg/kg) elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidol-induced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist), but not by mecamylamine (a nicotinic antagonist). In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±)-8-hydroxy-2-(di-n-propylamino)-tetralin (a 5-HT1A agonist), ritanserin (a 5-HT2 antagonist), and SB-258585 (a 5-HT6 antagonist). The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.
    Full-text · Article · Mar 2015 · Journal of Pharmacological Sciences
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    Full-text · Dataset · Jan 2015
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    ABSTRACT: The inwardly rectifying potassium (Kir) channel subunit Kir4.1 is specifically expressed in brain astrocytes and Kir4.1-containing channels (Kir4.1 channels) mediate astroglial spatial potassium (K +) buffering. Recent advances in Kir4.1 research revealed that Kir4.1 channels can serve as a novel therapeutic target for epilepsy. Specifically, reduced expression or dysfunction of Kir4.1 channels seems to be involved in generation of generalized tonic-clonic seizures (GTCS) in animal models of epilepsy and patients with temporal lobe epilepsy. In addition, recent clinical studies showed that loss-of-function mutations of human gene (KCNJ10) encoding Kir4.1 elicit " EAST " or " SeSAME " syndrome which manifests as GTCS and ataxia. Although the precise mechanisms remain to be clarified, it is suggested that dysfunction of Kir4.1 channels disrupts spatial K + buffering by astrocytes, elevates extracellular levels of K + and/or glutamate and causes abnormal excitation of neurons in the limbic regions and neocortex. All these findings suggest that agents that activate or up-regulateastroglialKir4.1 channels would be effective for epilepsy. In addition, docking simulation analysis usingtheKir4.1 homology model provide simportant information for designing new Kir4.1 ligands. Discovery of suchagents that activate or up-regulate Kir4.1 channels would be a novel approach for the treatment of epilepsy.
    Full-text · Article · Jan 2015
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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.
    Full-text · Article · Jan 2014
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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.
    Full-text · Article · Dec 2013 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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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.
    Full-text · Article · Oct 2013 · Neuroscience Research
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    Yukihiro Ohno · Saki Shimizu · Kentaro Tokudome
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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.
    Full-text · Article · Sep 2013 · Biological & Pharmaceutical Bulletin
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    Saki Shimizu · Yuto Mizuguchi · Yukihiro Ohno
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    ABSTRACT: Patients with schizophrenia exhibit various clinical symptoms including positive and negative symptoms, neurocognitive impairments and mood disturbances. Although a series of second generation antipsychotics (SGAs)(e.g.,risperidone,olanzapine and quetiapine)have been developed in the past two decades, clinical reports do not necessarily show advantages over first generation antipsychotics (FGAs) in the treatment of schizophrenia,especially intheir efficacy against cognitive impairment and ability to cause extrapyramidal side effects (EPS). Recently, several lines of studies have revealed therapeutic roles of 5-HT receptors in modulatingcognitive impairmentsand extrapyramidal motor disorders. Specifically, inhibition of 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT4 receptors alleviates cognitive impairments(e.g., deficits in learning and memory). In addition, stimulation of5-HT1A receptors or inhibition of 5-HT3 and 5-HT6 receptors as well as 5-HT2A/2C receptors can ameliorate extrapyramidal motor disorders. Thus, controlling the activity of 5-HT1A, 5-HT3or 5-HT6 receptors seems to provide benefits by bothalleviating cognitive impairments and reducing antipsychotic-induced EPS. This article reviews the functional rolesand mechanisms of 5-HT receptors in the treatment of schizophrenia, focusing on theserotonergicmodulation of cognitive and extrapyramidal motor functions, and illustrates future therapeutic strategies.
    Full-text · Article · Jul 2013 · CNS & neurological disorders drug targets
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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.
    Full-text · Article · Jul 2013 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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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.
    Full-text · Article · Jul 2013 · Frontiers in Cellular Neuroscience
  • 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.
    No preview · Chapter · Jul 2013
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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.
    Full-text · Article · Apr 2013 · Brain research
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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.
    Full-text · Article · Feb 2013 · Aging and Disease
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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.
    No preview · Chapter · Jan 2013
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    Yukihiro Ohno · Ayaka Tatara · Saki Shimizu · Masashi Sasa
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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.
    Full-text · Chapter · Jul 2012
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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.
    Full-text · Article · May 2012 · Neuropharmacology
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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.
    Full-text · Article · Apr 2012 · Progress in Neuro-Psychopharmacology and Biological Psychiatry