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Functional alteration in high voltage-gated calcium channels in drug dependence and elucidation of its mechanisms.

Research Project

Project/Area Number 14570095
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKawasaki Medical School

Principal Investigator

KATSURA Masashi  Kawasaki Medical School, School of Medicine, Assistant Professor, 医学部, 講師 (80204452)

Co-Investigator(Kenkyū-buntansha) WATANABE Satoru  Kawasaki Medical School, School of Medicine, Assistant Professor, 医学部, 講師 (90069055)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsDrug dependence / Abused drugs / Diazepam binding inhibitor / Cerebral cortical neurons / Calcium influx / Up-regulation / Protein phosphorvlation / High voltage-gated calcium channels / カルモデュリン / 電位依存性カルシウムチャネル / 大脳皮質神経細胞 / アルコール / モルヒネ / ニコチン
Research Abstract

Neuropharmacological mechanisms underlying development of drug dependence and withdrawal syndrome remain unclear at present. Several clinical features of withdrawal syndrome are considered to be common(i.e. anxiety) among patients with drug dependence induced by different drugs of abuse. In the present study, we have investigated functional alterations in diazepam binding inhibitor(DBI), an endogenous anxiogenic neuropeptide, in drug dependence and its withdrawal symptom. The levels of DBI protein and its mRNA significantly increased in the brains from mice dependent on alcohol, nicotine and morphine, and abrupt cessation of these drugs facilitated further increase in DBI expression. Similar patterns of DBI expression were observed in the neurons after sustained exposure to these drugs and its removal from culture medium. Sustained exposure of the neurons to abused drugs significantly increased the KC1(30mM)-induced[^<45>Ca^<2+>]influx and enhanced expression of α1 and α2/δ1 subunits for L-type high voltage-gated Ca^<2+> channels(HVCCs). In addition, the increase in DBI expression by drugs of abuse was completely blocked by L-type HVCC inhibitors. However, the increases in expression of L-type HVCCs after sustained exposures to drugs of abuse were not abolished by inhibitors for protein kinase A,C and CaM kinase II, respectiverly. These data indicate that up-regulation of L-type HVCCs, which causes increase in DBI expression, is considered to be a common biochemical process in drug dependence induced by different drugs of abuse.

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report

Research Products

(34 results)

All Other

All Publications (34 results)

  • [Publications] Katsura, M. et al.: "Up-regulation of L-type voltage-dependent calcium channels after long term exposure to nicotine in cerebral cortical neurons."Journal of Biological Chemistry. 277. 7979-7988 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Psychological stress, but not physical stress, causes increase in diazepam binding inhibitor (DBI) mRNA expression in mouse brains."Brain Research Molecular Brain Research. 104. 103-109 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Functional significance of nitric oxide in ionomycin-evoked [^3H]GABA release from mouse cerebral cortical neurons."Journal of Neurochemistry. 81. 130-141 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohkuma, S. et al.: "Protracted withdrawal syndrome--special reference to alteration of endogenous anxiety-inducing substances in the brain."Jpn.J.Neuropsychopharmacol.. 22. 203 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Up-regulation of high voltage gated calcium channels in nicotine dependence."Jpn.J.Neuropsychopharmacol.. 22. 208 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 大熊誠太郎, 桂 昌司: "新しい睡眠薬(ゾルピデム、クアゼパム)の薬理学特性"精神医学. 44. 305-311 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mohri, Y. et al.: "L-Type high voltage-gated calcium channels cause increase in diazepam binding inhibitor mRNA expression after sustained exposure to ethanol in mouse cerebral cortical neurons."Brain Research Molecular Brain Research. 113. 52-56 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 桂 昌司: "薬物依存形成におけるdiazepam binding inhibltor(DBI)発現とL型電位依存性カルシウムチャネルの機能的関連性"神経化学. 42. 47-59 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Continuous exposure to nitric oxide enhances diazepam binding inhibitor mRNA expression in mouse cerebral cortical neurons."Brain Research Molecular Brain Research. 124. 29-39 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohsawa, Y. et al.: "Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity."Human Molecular Genetics. 13. 151-157 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Pharmacological basis for management of drug dependence."Ann.New York Acad.Sci.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Functional relationship of diazepam binding inhibitor to L-type high voltage-gated calcium channels in alcohol dependence."Meth.Find.Exp.Clin.Pharmacol.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 大熊誠太郎, 桂 昌司: "コア・カリキュラム対応 医学一般"金芳堂. 412 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 大熊誠太郎, 桂 昌司: "6.モルヒネ依存とアミノ酸神経伝達"東北大学出版. 186 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Up-regulation of L-type voltage-dependent calcium channels after long term exposure to nicotine in cerebral cortical neurons."Journal of Biological Chemistry. 277. 7979-7988 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Psychological stress, but not physical stress, causes increase in diazepam binding inhibitor(DBI) mRNA expression in mouse brains."Brain Research Molecular Brain Research. 104. 103-109 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Functional significance of nitric oxide in ionomycin-evoked [^3H]GABA release from mouse cerebral cortical neurons."Journal of Neurochemistry. 81. 131-140 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mohri, Y. et al.: "L-Type high voltage-gated calcium channels cause increase in diazepam binding inhibitor mRNA expression after sustained exposure to ethanol in mouse cerebral cortical neurons."Brain Research Molecular Brain Research. 113. 52-56 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Continuous exposure to nitric oxide enhances diazepam binding inhibitor mRNA expression in mouse cerebral cortical neurons."Brain Research Molecular Brain Research. 124. 29-39 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ohsawa, Y. et al.: "Overexpression of P104L mutant cayeolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity."Human Molecular Genetics. 13. 151-157 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Pharmacological basis for management of drug dependence."Ann.New York Acad.Sci.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Katsura, M. et al.: "Functional relationship of diazepam binding inhibitor to L-type high voltage-gated calcium channels in alcohol dependence."Meth.Find.ExClin.Pharmacol.. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mohri Y. et al.: "L-Type high voltage-gated calcium channels cause an increase in diazepam binding Inhibitor mRNA expression after sustained exposure to ethanol in mouse cerebral cortical neurons."Brain Res.Mol.Brain Res.. 113. 52-56 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 桂 昌司: "薬物依存形成におけるdiazepam binding inhibitor(DBI)発現とL型電位依存性カルシウムチャネルの機能的関連性"神経化学. 42. 47-59 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 大熊誠太郎, 桂 昌司: "4.脳細胞分離・培養法"生物薬科学実験講座 神経(脳)II. 11. 30-53 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ohsawa, Y. et al.: "Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity."Human Mol.Gen.. 13. 151-157 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Katsura, M. et al.: "Continuous exposure to nitric oxide enhances diazepam binding inhibitor mRNA expression in mouse cerebral cortical neurons."Brain Res.Mol.Brain Res.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Katsura, M., Ohkuma, S.: "Pharmacological basis for management of drug dependence."Ann.New York Acad.Sci.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 大熊誠太郎, 桂 昌司(分担): "覚せい剤精神病と麻薬依存(佐藤光源, 櫻井映子編)"東北大学出版会. 186 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Katsura, M. et al.: "Up-regulation of L-type voltage-dependent calcium channels after long term exposure to nicotine in cerebral cortical neurons"Journal of Biological Chemistry. 277. 7979-7988 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Katsura, M. et al.: "Functional significance of nitric oxide in ionomycin-evoked[^3H]GABA release from mouse cerebral cortical neurons"Journal of Neurochemistry. 81. 130-141 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Katsura, M. et al.: "Psychological stress, but not physical stress, causes increase in diazepam binding inhibitor (DBI) mRNA expression in mouse brains"Molecular Brain Research. 104. 103-109 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mohri, Y. et al.: "L-Type high voltage-gated calcium channels cause increase in diazepam binding inhibitor mRNA expression after sustained exposure to ethanol in mouse cerebral cortical neurons"Molecular Brain Research. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 大熊誠太郎, 桂 昌司: "コア・カリキュラム対応 医学一般"金芳堂. 412 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-03-31   Modified: 2016-04-21  

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