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Identification of common biological markers underlying establishment of drug dependence and an attempt to develop pharmacogenomic therapy

Research Project

Project/Area Number 18500302
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionKawasaki Medical School

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) SHIBASAKI Masahiro  Kawasaki Medical School, School of Medicine, Research Assistant (80412162)
OHKUMA Seitaro  Kawasaki Medical School, School of Medicine, Professor (30152086)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,990,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsDrug dependence / Reward effects / Ryanodine receptors / IP3 receptors / Cav1.2 subunits / Cav β subunits / Calcium-induced calcium release / High voltage-gated calcium channels / L型高電位開口性カルシウムチャネル / 依存性薬物 / Ca^<2+>センサー蛋白 / 細胞内カルシウム濃度 / 初代培養神経細胞
Research Abstract

In this research project, we have been carried out to identify the common biological markers underlying establishment of drug dependence and an attempt to develop pharmacogenomic therapy.
Functional alterations in L-type high voltage-gated calcium channels (Cav1) after short-term (24h) exposure of mouse cerebrocortical neurons to drugs of abuse were examined as compared with those in psychological dependent mouse brains. KC1 (30 mM)-stimulated [^<45>Ca^<2+>] influx into the neurons increased with increasing the duration of the drugs exposure and its concentrations. This enhancement was completely abolished by Cav1 inhibitors, and antagonists for ryanodine and IP_3 receptors. Cav1.2 and Cav α2-δ proteins were increased in abused drugs-treated neurons. Increased binding of [^<3>H]PN200-110 after 24 h exposure to drugs of abuse was due to decreased Kd value. Similar changes in the binding parameters and protein expressions were obtained in cerebral cortices as well as nucleus accumbens fro … More m psychological dependent mice. These results indicate that stimulation of calcium-induced calcium release by ryanodine receptors and subsequent activations of IP_3 receptors induces Cav1 up-regulation.
Furthermore, we examined the functional involvement of accessory proteins of Cav 3 subunits in ethanol (EtOH)-induced Cav1 up-regulation. Short-term exposure of the neurons to EtOH significantly increased in Cav β3 subunit levels, whereas Cav β1, β2 and β4 subunits showed no changes. High potassium-stimulated [^<45>Ca^<2+>] influx into the neurons significantly increased by EtOH exposure and this increase was not observed in the neurons pretreated with morpholino oligomers specific for Cav β3 subunits. Decreased Kd value of [^3H] P: N200-110 after EtOH exposure was also abolished by Cav β3 subunits knockdown. Similar changes in protein expressions were obtained in cerebral cortices from psychological dependent mice. These results indicate that short-term exposure of the neurons to EtOH up-regulates Cav1 functions via increased expression of Cav β3 subunit proteins in the neuronal membrane. Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (34 results)

All 2008 2007 2006

All Journal Article (25 results) (of which Peer Reviewed: 9 results) Presentation (8 results) Book (1 results)

  • [Journal Article] Up-regulation of L-type high voltage-gated calcium channel subunits by sustained exposure to 1,4 and 1,5-benzodiazepines in cerebrocortical neuron2007

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

      Journal of Neurochemistry 103

      Pages: 2518-2528

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Regional differences of L-type high voltage-gated calcium channel subunit expression in the mouse brain after chronic morphine treatment2007

    • Author(s)
      Shibasaki, M.
    • Journal Title

      Journal of Pharmacological Science 105

      Pages: 177-183

    • NAID

      10024316308

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Increase in diazepam binding inhibitor expression by sustained morphine exposure is mediated via μ-opioid receptors in primary cultures of mouse cerebral cortical neurons2007

    • Author(s)
      Shibasaki, M.
    • Journal Title

      Journal of Neuroscience Research 85

      Pages: 2971-2980

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Changes in intracellular calcium dynamics observed during the development of alcohol psychological and physical dependence.2007

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

      Jpn. J. Alcohol & Drug Dependence 42

      Pages: 59-66

    • NAID

      10020157950

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Difference in mechanisms between psychological and physical dependence.2007

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

      Jpn. J. Alcohol & Drug Dependence 42

      Pages: 481-486

    • NAID

      10019782726

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Nateglinide and mitiglinide, but not sulfonylureas, induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum.2007

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

      J. Pharmacol. Exp. Ther. 322

      Pages: 1-7

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Up-regulation of L-type high voltage-gated calcium channel subunits by sustained exposure to 1, 4 and 1, 5-benzodiazepines in cerebrocortical neuron.2007

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

      J. Neurochem. 103

      Pages: 2518-2528

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Regional differences of L-type high voltage-gated calcium channel subunit expression in the mouse brain after chronic morphine treatment.2007

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

      J. Pharmacol. Sci. 105

      Pages: 177-183

    • NAID

      10024316308

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Increase in diazepam binding inhibitor expression by sustained morphine exposure is mediated via t-opioid receptors in primary cultures of mouse cerebral cortical neurons.2007

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

      J. Neurosci. Res. 85

      Pages: 2971-2980

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Up-regulation of L-type high voltage-gated calcium channel subunits by sustained exposure to 1,4-and 1,5-benzodiazepines in cerebrocortical neuron2007

    • Author(s)
      Katsura M.
    • Journal Title

      Journal of Neurochemistry 103

      Pages: 2518-2828

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Increase in expression of α1 and α2/δ1 subunits of L-type high voltage-gated calcium hannels after sustained ethanol exposure in cerebral cortical neurons2007

    • Author(s)
      Katsura M.
    • Journal Title

      Journal of Pharmacological Science 102

      Pages: 221-230

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Changes in intracellular calcium dynamics observed during the development of alcohol psychological and physical dependence2007

    • Author(s)
      Katsura M.
    • Journal Title

      Nikon Arukoru Yakubutsu Igakkai Zasshi 42

      Pages: 59-66

    • NAID

      10020157950

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 細胞内カルシウム動態変化からみたアルコール精神依存および身体依存形成2007

    • Author(s)
      桂 昌司
    • Journal Title

      日本アルコール・薬物医学会雑誌 42

      Pages: 59-66

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Increase in diazepam binding inhibitor expression by sustained morphine exposure is mediated via μ-opioid receptors in mouse cerebral cortical neurons.2007

    • Author(s)
      Shibasaki, M.
    • Journal Title

      Journal of Neuroscience Research (In press)

    • Related Report
      2006 Annual Research Report
  • [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 neurons2006

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

      Journal of Pharmacological Science 105

      Pages: 221-230

    • NAID

      10020345687

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Up-regulated L-type high voltage-gated calcium channels cause increase in diazepam binding inhibitor induced by sustained morphine exposure in mouse cerebrocortical neurons2006

    • Author(s)
      Shibasaki, M.
    • Journal Title

      Life Science 80

      Pages: 166-172

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Expression of β-adrenergic receptor up-regulation is mediated by two different processes2006

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

      Brain Research 1112

      Pages: 114-125

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Expression of β-adrenergic receptor up-regulation is mediated by two different processes.2006

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

      Brain Res. 1112

      Pages: 114-25

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] First phase of glucose-stimulated insulin secretion from MIN 6 cells does not always require extracellular calcium influx.2006

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

      J. Pharmacol. Sci. 101

      Pages: 293-302

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Up-regulated L-type high voltage-gated calcium channels cause increase in diazepam binding inhibitor induced by sustained morphine exposure in mouse cerebrocortical neurons.2006

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

      Life Sci. 80

      Pages: 166-72

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 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)
      Katsura, M., et. al.
    • Journal Title

      J. Pharmacol. Sci. 102

      Pages: 221-30

    • NAID

      10020345687

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Expression of β-adrenergic receptor up-regulation is mediated by two different processes.2006

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

      Brain Research 1112

      Pages: 114-125

    • Related Report
      2006 Annual Research Report
  • [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)
      Katsura, M.
    • Journal Title

      Journal of Pharmacological Sciences 102

      Pages: 221-230

    • NAID

      10020345687

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Up-regulated L-type high voltage-gated calcium channels cause increase in diazepam binding inhibitor induced by sustained morphine exposure in mouse cerebrocortical neurons.2006

    • Author(s)
      Shibasaki, M.
    • Journal Title

      Life Science 80

      Pages: 166-172

    • Related Report
      2006 Annual Research Report
  • [Journal Article] First phase of glucose-stimulated insulin secretion from MIN 6 cells does not always require extracellular calcium influx.2006

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

      Journal of Pharmacological Sciences 101

      Pages: 293-302

    • Related Report
      2006 Annual Research Report
  • [Presentation] Functional involvement of high voltage-gated calcium channels (HVCC) β subunits in alcohol (EtOH) psychological dependence2008

    • Author(s)
      Katsura, M.
    • Organizer
      The 81th Annual Meeting of The Japanese Pharmacological Society
    • Place of Presentation
      Yokohama,JAPAN
    • Year and Date
      2008-03-18
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Functional involvement of high voltage-gated calcium channels (HVCC) β subunits in alcohol (EtOH) psychological dependence.2008

    • Author(s)
      Katsura, M., et. al.
    • Organizer
      The 81th Annual Meeting of The Japanese Pharmacological Society
    • Place of Presentation
      Yokohama
    • Year and Date
      2008-03-18
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Functional involvement of high voltage gated calcium channel(HVCC)B subunits in alcohol(EtOH)psychological dependence2008

    • Author(s)
      Katsura M.
    • Organizer
      The 81th Annual Meeting of The Japanese Pharmacological Society
    • Place of Presentation
      Yokohama,Japan
    • Year and Date
      2008-03-18
    • Related Report
      2007 Annual Research Report
  • [Presentation] Biological research on the protracted withdrawal syndrome (PWS)-relationship between CSF level of DBI, CRH and score of clinical symptom evaluation scale-2007

    • Author(s)
      Hori, T., et. al.
    • Organizer
      Neuroscience Meeting 2007
    • Place of Presentation
      San Diego
    • Year and Date
      2007-11-05
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Intracellular calcium dynamics in ethanol psychological dependence.2007

    • Author(s)
      Katsura, M., et. al.
    • Organizer
      Research Conference on Alcohol and Health in Shanghai 2007
    • Place of Presentation
      Shanghai
    • Year and Date
      2007-06-19
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Morphine (MOR) up-regulates L-type high voltage-gated calcium channels (HVCCs) through ryanodine receptor activation in mouse brains.2007

    • Author(s)
      Katsura, M., et. al.
    • Organizer
      The 80th Annual Meeting of The Japanese Pharmacological Society
    • Place of Presentation
      Nagoya
    • Year and Date
      2007-03-14
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Difference in mechanisms underlying physical and psychological dependence2006

    • Author(s)
      Katsura, M.
    • Organizer
      The 36th Annual Meeting of The Japanese Society of Neuropsychopharmacology
    • Place of Presentation
      Nagoya,JAPAN
    • Year and Date
      2006-09-10
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Difference in mechanisms underlying physical and psychological dependence.2006

    • Author(s)
      Katsura, M., et. al.
    • Organizer
      The 36th Annual Meeting of The Japanese Society of Neuropsychopharmacology
    • Place of Presentation
      Nagoya
    • Year and Date
      2006-09-05
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] グッドマン・ギルマン薬理書(上) 薬物治療の基礎と臨床(第11版)2007

    • Author(s)
      大熊 誠太郎
    • Total Pages
      1206
    • Publisher
      廣川書店
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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