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An attempt to develop pharmacogenomic therapy and prevention of drug dependence.

Research Project

Project/Area Number 15390175
Research Category

Grant-in-Aid for Scientific Research (B)

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

Principal Investigator

OHKUMA Seitaro  Kawasaki Medical School, School of Medicine, Professor, 医学部, 教授 (30152086)

Co-Investigator(Kenkyū-buntansha) KATSURA Masashi  Kawasaki Medical School, School of Medicine, Assistant Professor, 医学部, 講師 (80204452)
WATANABE Satoru  Kawasaki Medical School, School of Medicine, Assistant Professor, 医学部, 講師 (90069055)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2005: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2004: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2003: ¥6,600,000 (Direct Cost: ¥6,600,000)
Keywordsdrug dependence / High voltage-gated Ca channels / alcohol / methamphetamine / ryanodine trceptors / conditioned place preference / methanphetamine / ethanol / L型高電位開口性カルシウムチャネル / [3H]diltiazem結合 / エタノール / モルヒネ / ニコチン / アンフェタミン / α1サブユニット / ジアゼパム結合阻害蛋白質 / L型高電位開口性Ca^<2+>チャネル / アルコール(エタノール) / [^3H]diltiazem結合
Research Abstract

This research project has been carried out to develop pharmacogenomic therapy and prevention of drug dependence.
Chronic administrations of ethanol, morphine, and nicotine produced increase of Bmax values of [^3H] diltiazem binding to the particulate fractions from animal cerebral cortex and increased expressions of α1C and α1D subunits of L-type high voltage-gated calcium channels (HVCCs) in animal cerebral cortex. Similarly, long-term exposure of cerebrocortical neurons in primary culture to these drugs of abuse also increased Bmax values of [^3H]diltiazem binding and expressions of α1C and α1D subunits of L-type HVCCs. These alterations of L-type HVCC subunit expressions followed the increased their mRNA expressions, suggesting that the L-type HVCC functions associated with increase in their protein molecules are involved in development of physical dependence.
On the other hand, methamphetamine(MET) and cocaine produced decreased Kd value of binding with no changes of L-type HVCC subu … More nit expressions in animal cerebral cortex and cerebral cortical neurons. In conditioned place preference(CPP) test, intraventricular administration of nifedipine and dantrolene abolished increased CPP by MET and enhanced L-type HVCC functions described above. In cerebrocortical neurons, exposure to nifedipine and dantrolene also abolished the alteration of L-type HVCC functions induced by MET and cocaine, while the changes of L-type HVCCs associated with increased expressions of their subunits were not affected by similar treatments. In addition, sustained exposure to MET and cocaine significantly enhanced ryanodine-induced increase of calcium oscillation in cerebrocortical neurons when examining with fura-2, suggesting the lonf-term exposure to MET and cocaine enhanced ryanodine receptors through which calcium-induced calcium release. These changes in intracellular calcium dynamics are considered to participate in psychological dependence by MET and cocains. In addition, the differences in L-type HVCC subunit expression patterns and in response of L-type HVCC subunit expression to dantrolene are considered to suggest different pathogenesis between physical and psychological dependence. Less

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (50 results)

All 2006 2005 2004 2003 Other

All Journal Article (39 results) Book (4 results) Publications (7 results)

  • [Journal Article] Increase in expression of α1 and α2/δ subunits of L-type high voltage-gated calcium channels after sustained ethanol exposure in cerebral cortical neurons.2006

    • Author(s)
      Hayashida, S. et al.
    • Journal Title

      Brain Res. Mol. Brain Res. (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] First phase of glucose-stimulated insulin secretion from MIN 6 cells does not always require extracelluar calcium influx.2006

    • Author(s)
      Shigeto, M. et al.
    • Journal Title

      J. Pharmacol. Sci. (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Increase in expression of α1 and α2/δ1 subunits of L-type high voltage-gated calcium channels after sustained ethanol exposure in cerebral cortical neurons.2006

    • Author(s)
      Hayashida, S.et al.
    • Journal Title

      Brain Res.Mol.Brain Res. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] First phase of glucose-stimulated insulin secretin from MIN 6 cells does not always require extracelluar calcium influx.2006

    • Author(s)
      Shigeto, M.et al.
    • Journal Title

      J.Pharmacol.Sci. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] アルコール長期曝露によるL型高電位開口性カルシウムチャネルの機能変化とその意義2005

    • Author(s)
      桂 昌司 他
    • Journal Title

      日本アルコール・薬物医学会雑誌 40

      Pages: 205-212

    • NAID

      10016593172

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Chronic nicotine treatment upregulates L-type high voltage-gated calcium channels.2005

    • Author(s)
      Katsura, M. et al.
    • Journal Title

      J. Pharmacol. Sci. 97

      Pages: 344-347

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/ reperfusion injury in canine coronary microcirculation in vivo.2005

    • Author(s)
      Yada, T. et al.
    • Journal Title

      J. Am. Coll. Cardiol. 45

      Pages: 599-607

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 【アルコール依存症 最近の話題】アルコール症の薬物療法2005

    • Author(s)
      大熊誠太郎 他
    • Journal Title

      最新精神医学 10

      Pages: 375-381

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ethanol physical dependence is accompanied by up-regulated expression of L-type high voltage-gated calcium channel α1 subunits in mouse brain.2005

    • Author(s)
      Katsura, M. et al.
    • Journal Title

      Brain Res. 1039

      Pages: 211-215

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Increased expression of L-type high voltage-gated calcium channel α1 and α2/δ subunits in mouse brain after chronic nicotine administration.2005

    • Author(s)
      Hayashida, S. et al.
    • Journal Title

      Brain Res. Mol. Brain Res. 135

      Pages: 280-284

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ethanol physical dependence is accompanied by up-regulated expression of L-type high voltage-gated calcium channel α1 subunits in mouse brain.2005

    • Author(s)
      Katsura, M.et al.
    • Journal Title

      Brain Res. 1039

      Pages: 211-215

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo.2005

    • Author(s)
      Yada, T.et al.
    • Journal Title

      J.Am.Coll.Cardiol. 45

      Pages: 599-607

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Functional Proteins Involved in Regulation of Intracellular Ca^<2+> for Drug Development : Chronic Nicotine Treatment Upregulates L-Type High Voltage-Gated Calcium Channels.2005

    • Author(s)
      Katsura, M.et al.
    • Journal Title

      J.Pharmacol.Sci. 97(3)

      Pages: 344-347

    • NAID

      10025726667

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Increased expression of L-type high voltage-gated calcium channel α1 and α2/δ subunits in mouse brain after chronic nicotine administration.2005

    • Author(s)
      Hayashida, S.et al.
    • Journal Title

      Brain Res.Mol.Brain Res. 135(1-2)

      Pages: 280-284

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Beneficial effect of hydroxyfasudil, a specific Rho-kinase inhibitor, on ischemia/reperfusion injury in canine coronary microcirculation in vivo.2005

    • Author(s)
      Yada, T. et al.
    • Journal Title

      J.Am.Coll.Cardiol. 45

      Pages: 599-607

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Chronic nicotine treatment upregulates L-type high voltage-gated calcium channels.2005

    • Author(s)
      Katsura, M., Ohkuma, S.
    • Journal Title

      J.Pharmacol.Sci. 97

      Pages: 344-347

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Increased expression of L-type high voltage-gated calcium channel al and α2/δ subunits in mouse brain after chronic nicotine administration.2005

    • Author(s)
      Hayashida, S. et al.
    • Journal Title

      Brain Res.Mol.Brain Res. 135

      Pages: 280-284

    • Related Report
      2005 Annual Research Report
  • [Journal Article] アルコール長期曝露によるL型高電位開口性カルシウムチャネルの機能変化とその意義2005

    • Author(s)
      桂 昌司, 大熊誠太郎
    • Journal Title

      日本アルコール・薬物医学会雑誌 40

      Pages: 205-212

    • NAID

      10016593172

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 【アルコール依存症最近の話題】アルコール症の薬物療法2005

    • Author(s)
      大熊誠太郎, 桂 昌司
    • Journal Title

      最新精神医学雑誌 10

      Pages: 375-381

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Increased expression of L-type high voltage-gated calcium channel α1 and α2/δ subunits in mouse brain after chronic nicotine administration2005

    • Author(s)
      Hayashida, S., et al.
    • Journal Title

      Brain Res.Mol.Brain Res. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Ethanol physical dependence is accompanied by up-regulated expression of L-type high voltage-gated calcium channel α1 subunits in mouse brain2005

    • Author(s)
      Katsura, M., et al.
    • Journal Title

      Brain Res. (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.2004

    • Author(s)
      Ohsawa, Y. et al.
    • Journal Title

      Human Mol. Genet. 13

      Pages: 151-157

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Functional relationship of diazepam binding inhibitor to L-type high voltage-gated calcium channels in alcohol dependence..2004

    • Author(s)
      Katsura, M. et al.
    • Journal Title

      Meth. Find. Exp. Clin. Pharmacol. 26

      Pages: 95-96

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Pharmacological basis for management of drug dependence.2004

    • Author(s)
      Katsura, M. et al.
    • Journal Title

      Ann. N. Y. Acad. Sci. 1025

      Pages: 578-583

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Continuous exposure to nitric oxide enhances diazepam binding inhibitor mRNA expression in mouse cerebral cortical neurons.2004

    • Author(s)
      Katsura, M. et al.
    • Journal Title

      Brain Res. Mol. Brain Res. 124

      Pages: 29-39

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Chemotherapeutic targeting of etoposide various tissues on the basis of polyamine level.2004

    • Author(s)
      Watanabe, S. et al.
    • Journal Title

      J. Drug Target 12

      Pages: 57-62

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 〔特集 : 不安障害のメカニズムと治療法の発展〕 内在性不安誘発物質の脳内発現変化とその意義.2004

    • Author(s)
      桂 昌司 他
    • Journal Title

      神経精神薬理学雑誌 24

      Pages: 119-123

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Pharmacological basis for management of drug dependence.2004

    • Author(s)
      Katsura, M.et al.
    • Journal Title

      Ann.New York Acad.Sci. 1025

      Pages: 578-583

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Continuous exposure to nitric oxide enhances diazepam binding inhibitor mRNA expression in mouse cerebral cortical neurons.2004

    • Author(s)
      Katsura, M.et al.
    • Journal Title

      Brain Res.Mol.Brain Res. 124

      Pages: 29-39

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity.2004

    • Author(s)
      Ohsawa, Y.et al.
    • Journal Title

      Human Mol.Genet. 13

      Pages: 151-157

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Functional relationship of diazepam binding inhibitor to L-type high voltage-gated calcium channels in alcohol dependence.2004

    • Author(s)
      Katsura, M.et al.
    • Journal Title

      Meth.Find.Exp.Clin.Pharmacol. 26(Suppl.2)

      Pages: 95-96

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Chemotherapeutic targeting of etoposide various tissues on the basis of polyamine level.2004

    • Author(s)
      Watanabe, S.et al.
    • Journal Title

      J.Drug Target 12

      Pages: 57-62

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Continuous exposure to nitric oxide enhances diazepam binding inhibitor mRNA expression in mouse cerebral cortical neurons2004

    • Author(s)
      Katsura, M., et al.
    • Journal Title

      Brain Res.Mol.Brain Res. 124

      Pages: 29-39

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 内在性不安誘発物質の脳内発現変化とその意義2004

    • Author(s)
      桂 昌司, 大熊 誠太郎
    • Journal Title

      日本神経精神薬理学雑誌 24

      Pages: 119-123

    • NAID

      10013150185

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Pharmacological basis for management of drug dependence2004

    • Author(s)
      Katsura, M., Ohkuma, S.
    • Journal Title

      Ann.N.Y.Acad.Sci. 1025

      Pages: 578-583

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Chemotherapeutic targeting of etoposide to various tissues on the basis of polyamine level2004

    • Author(s)
      Watanabe, S., et al.
    • Journal Title

      J.Drug Target. 12

      Pages: 57-62

    • Related Report
      2004 Annual Research Report
  • [Journal Article] L-Type high voltage-grated calcium channels cause an increase in diazepam binding inhibitor mRNA expression after sustained exposure to ethanol in mouse cerebral cortical neurons.2003

    • Author(s)
      Mohri, Y. et al.
    • Journal Title

      Brain Res. Mol. Brain Res. 113

      Pages: 52-56

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 薬物依存形成におけるdiazepam binding inhibitor (DBI)表現とL型電位依存性カルシウムチャネルの機能的関連性。2003

    • Author(s)
      桂 昌司
    • Journal Title

      神経科学 42

      Pages: 47-59

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 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.2003

    • Author(s)
      Mohri, Y.et al.
    • Journal Title

      Brain Res.Mol.Brain Res. 113

      Pages: 52-56

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] コア・カリキュラム対応 医学一般〔改訂2版〕(今西二郎 編)2005

    • Author(s)
      大熊誠太郎, 桂 昌司(分担)
    • Total Pages
      346
    • Publisher
      金芳堂
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 医学薬理学(改訂4版)(遠藤政夫、栗山欣弥、大熊誠太郎、田中利夫、樋口宗史 編)2005

    • Author(s)
      大熊誠太郎
    • Total Pages
      739
    • Publisher
      南山堂
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 医科薬理学2005

    • Author(s)
      大熊誠太郎
    • Total Pages
      739
    • Publisher
      南山堂
    • Related Report
      2005 Annual Research Report
  • [Book] 覚せい剤精神病と麻薬依存(佐藤光源、櫻井映子編)2004

    • Author(s)
      大熊誠太郎, 桂昌司(分担)
    • Total Pages
      186
    • Publisher
      東北大学出版会
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 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

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Published: 2003-04-01   Modified: 2016-04-21  

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