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Study on Molecular Pathophysiology of Schizophrenia

Research Project

Project/Area Number 17390316
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionChiba University

Principal Investigator

HASHIMOTO Kenji  Chiba University, Center for Forensic Mental Health, Professor, 社会精神保健教育研究センター, 教授 (10189483)

Co-Investigator(Kenkyū-buntansha) YOSHIKAWA Takeo  RIKEN Brain Science Institute, Team Leader, 脳科学研究所, チームリーダー (30249958)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2006: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000)
KeywordsNMDA receptor / Schizophrenia / Nicotine Receptor / Sigma Receptor / Tropisetron / Glutamate / Cognitive deficits / Fluvoxamine / グリア細胞 / フャンサイクルジン / グリシントランスポーター
Research Abstract

Several lines of evidence suggest that dysfunction of glutamatergic transmission via NMDA receptor play a role in the pathophysiology of schizophrenia. Therefore, NMDA receptor antagonist phencyclidine (PCP) have been widely used as animal model of schizophrenia. We reported that PCP-induced cognitive deficits in mice could be attenuated by subsequent subchronic administration of clozapine, but not haloperidol.
This study was undertaken to examine the effects of the selective serotonin reuptake inhibitor fluvoxamine on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day). Furthermore, t … More he effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S ; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice.
Next, we examined the effects of tropisetron, a 5-hydroxytryptamine (5-HT3) receptor antagonist and α7 nicotinic receptor agonist, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2-weeks) administration of tropisetron, but not ondansetron. Effects of tropisetron were significantly antagonized by co-administration of the α7 nicotinic receptor antagonist methyllycaconitine, suggesting the role of α7 nicotinic receptors in the active mechanisms of tropisetron. These findings suggest that sigma-1 receptor agonists and α7 nicotinic receptor agonists such as tropisetron could be a potential therapeutic drug for cognitive deficits in schizophrenic patients. Less

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (22 results)

All 2007 2006 2005

All Journal Article (22 results)

  • [Journal Article] Phencyclidine-Induced Cognitive Deficits in Mice are Improved by Subsequent Subchronic Administration of Fluvoxamine : Role of Sigma-1 Receptors.2007

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Neuropsychopharmacology 32・3

      Pages: 514-521

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Phencyclidine-Induced Cognitive Deficits in Mice are Improved by Subsequent Subchronic Administration of Fluvoxamine : Role of Sigma-1 Receptors.2007

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      32(3)

      Pages: 514-521

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Phencyclidine-Induced Cognitive Deficits in Mice are Improved by Subsequent Subchronic Administration of Fluvoxamine : Role of Sigma-1 Receptors.2007

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Neuropsychopharamacology 32・3

      Pages: 514-521

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Glycine transporter inhibitors as therapeutic agents for schizophrenia.2006

    • Author(s)
      Hashimoto K
    • Journal Title

      Recent Patents on CNS Drug Discovery 1

      Pages: 43-53

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring : a neurodevelopmental animal model of schizophrenia.2006

    • Author(s)
      Ozawa K. et al.
    • Journal Title

      Biol Psychiatry 15・59(6)

      Pages: 546-554

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Sigma receptor ligands : Possible applications as therapeutic drugs and as radiopharmaceuticals.2006

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Curr Pharm Des 12・30

      Pages: 3857-3876

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] The NMDA receptor hypofunction hypothesis for schizophrenia and glycine modulatory sites on the NMDA receptors as potential therapeutic drugs.2006

    • Author(s)
      Hashimoto K.
    • Journal Title

      Clin Psychopharmacol Neurosci 4・1

      Pages: 3-10

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron : Role of α7 nicotinic receptors.2006

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Eur J Pharmacol 28・553(1-3)

      Pages: 191-195

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Glycine transporter inhibitors as therapeutic agents for schizophrenia.2006

    • Author(s)
      Hashimoto K.
    • Journal Title

      Recent Patients on CNS Drug Discovery 1

      Pages: 43-53

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring : a neurodevelopmental animal model of schizophrenia.2006

    • Author(s)
      Ozawa K. et al.
    • Journal Title

      Biol Psychiatry 59(6)

      Pages: 546-554

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Possible applications as therapeutic drugs and as radiopharmaceuticals.2006

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Curr Pharm Des 12(30)

      Pages: 3857-3876

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The NMDA receptor hypofunction hypothesis for schizophrenia and glycine modulatory sites on the NMDA receptors as potential therapeutic drugs.2006

    • Author(s)
      Hashimoto K.
    • Journal Title

      4(1)

      Pages: 3-10

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron : Role of α7 nicotinic receptors.2006

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      553(1-3)

      Pages: 191-195

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of tropisetron : Role of α7 nicotinic receptors.2006

    • Author(s)
      Hashimoto K et al.
    • Journal Title

      Eur J Pharmacol 28・553(1-3)

      Pages: 191-195

    • Related Report
      2006 Annual Research Report
  • [Journal Article] The NMDA receptor hypofunction gypothesis for schizophrenia and glycine modulatory sites on the NMDA receptors as potential therapeutic drugs.2006

    • Author(s)
      Hashimoto K.
    • Journal Title

      Clin Psychopharmacol Neurosci 4・1

      Pages: 3-10

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Glycine transporter inhibitors as therapeutic agents for schizophrenia.2006

    • Author(s)
      Hashimoto K.
    • Journal Title

      Recent Patents on CNS Drug Discovery 1・

      Pages: 43-53

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Elevated glutamine/glutamate ratio in cerebrospinal fluid of first episode and drug naive schizophrenic patients.2005

    • Author(s)
      Hashimoto K et al.
    • Journal Title

      BMC Psychiatry 5・1

      Pages: 6-6

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Dysfunction of glia-neuron communication in pathophysiology of schizophrenia.2005

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Current Psychiatry Review 1・2

      Pages: 151-163

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels.2005

    • Author(s)
      Yamada K et al.
    • Journal Title

      Biological Psychiatry 57・12

      Pages: 1493-1503

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Reduced D-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients.2005

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Progress in Neuro-Psychopharmacology & Biological Psychiatry 29・5

      Pages: 767-769

    • Related Report
      2005 Annual Research Report
  • [Journal Article] α7 Nicotinic receptor agonists as potential therapeutic drugs for schizophrenia.2005

    • Author(s)
      Hashimoto K. et al.
    • Journal Title

      Current Medicinal Chemistry CNS Agents 5・3

      Pages: 171-184

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Analysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes.2005

    • Author(s)
      Iwayama Y et al.
    • Journal Title

      Neuroscience Letters 394・2

      Pages: 101-104

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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