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2004 Fiscal Year Final Research Report Summary

Study on the role of endogenous neurosteroids in the regulation of GABAergic function and pathophysiology of stress

Research Project

Project/Area Number 15591215
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionTOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY

Principal Investigator

MATSUMOTO Kinzo  Toyama Medical and Pharmaceutical University, Institute of Natural Medicine, Professor, 和漢薬研究所, 教授 (10114654)

Co-Investigator(Kenkyū-buntansha) TOHDA Michihisa  Toyama Medical and Pharmaceutical University, Institute of Natural Medicine, Associate Professor, 和漢薬研究所, 助教授 (20207525)
Project Period (FY) 2003 – 2004
Keywordsneurosteroid / allopregnanolone / social isolation stress / GABA_A receptor / aggressive behavior / fluoxetine / neuropsychiatric disorder / mice
Research Abstract

In this study, we investigated physiological and pathophysiological roles of an endogenous neurosteroid, allopregnanolone (ALLO), in the regulation of GABAergic system using protracted social isolation mice as an animal model with dysfunction of neurosteroidogenesis system. Social isolation stress and a 5α-reductase inhibitor SKF105111 (SKF) treatment significantly reduced a threshold dose of picrotoxin to induce convulsion in mice. The effect of SKF was significantly reversed by a small dose of ALLO. The present electrophysiological study revealed that the SKF treatment decreased GABA-induced Cl^-currents and GABA-mediated inhibitory postsynaptic currents in normal mice. Protracted social isolation of mice induced a decrease of brain ALLO content in an isolation period-dependent manner and the extent of the decrease was inversely related to the increase of aggressiveness in this animal group. S-and R-Fluoxetine, selective serotonin reuptake inhibitors, reduced ex vivo serotonin uptake into the brain tissue but there was no difference in the potency between these stereoisomers. On the other hand, both S-and R-fluoxetine mitigated aggressiveness and normalized brain ALLO level in socially isolated mice at lower doses than they inhibited serotonin reuptake. Therefore, our study suggested that the brain ALLO content physiologically upregulates the GABA receptor function and that social isolation stress-induces a reduction of brain ALLO probably causally related with the onset of aggression.

  • Research Products

    (11 results)

All 2005 2004 2003 Other

All Journal Article (11 results)

  • [Journal Article] ストレスと睡眠・情動障害:神経ステロイド・allopregnanolone系の関与2005

    • Author(s)
      松本欣三ほか
    • Journal Title

      日本薬理学雑誌 (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Social isolation stress-induced aggression in mice : a model to study the pharmacology of neurosteroidogenesis.2005

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

      STRESS (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Psychopathological roles of endogenous brain allopregnanolone : elucidation in a mouse model of protracted social isolation2004

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

      Methods and Findings in Experimental and Clinical Pharmacology 26(suppl.2)

      Pages: 85-86

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Psychopathological roles of endogenous brain allopregnanolone : elucidation in a mouse model of protracted social isolation.2004

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

      Methods and Findings in Exp.Clin.Pharmacol. 26(suppl.2)

      Pages: 85-86

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Long-term Social isolation enhances picrotoxin seizure susceptibility in mice : Upregulatory role of endogenous brain allopregnanolone in GABAergic systems2003

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

      Pharmacol.Biochem.Behav. 75

      Pages: 831-835

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] On the putative physiological role of allopregnanolone on GABAA receptor function2003

    • Author(s)
      Puia G.et al.
    • Journal Title

      Neuropharmacology 44

      Pages: 49-55

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine2003

    • Author(s)
      Pinna G. et al.
    • Journal Title

      Proc.Natl.Acad.Sci.USA 100

      Pages: 2035-2040

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] On the putative physiological role of allopregnanolone on GABA_A receptor function2003

    • Author(s)
      Puia G., et al.
    • Journal Title

      Neuropharmacology 44

      Pages: 49-55

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine.2003

    • Author(s)
      Pinna, G
    • Journal Title

      Proc.Natl.Acad.Sci.USA 100

      Pages: 2035-2040

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Stress and sleep/emotional disorder : possible involvement of neurosteroid allopregnanolone

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

      Folia Pharmacologica Japonica (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Social isolation stress-induced aggression in mice : a model to study the pharmacology of neurosteroidogenesis.

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

      STRESS (in press)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2006-07-11  

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