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報酬回路におけるモノアミン・オピオイド神経伝達の分子機構

Research Project

Project/Area Number 15029204
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTohoku University

Principal Investigator

曽良 一郎  東北大学, 大学院・医学系研究科, 教授 (40322713)

Co-Investigator(Kenkyū-buntansha) 沼地 陽太郎 (沼知 陽太郎)  東北大学, 大学院・医学系研究科, 助教授 (00261636)
池田 和隆  (財)東京都医学研究機構, 東京都精神医学総合研究所, 主任研究員 (60281656)
山本 秀子  (財)東京都医学研究機構, 東京都精神医学総合研究所, 研究員 (60211645)
城戸 幹太  東北大学, 大学院・歯学系研究科, 助手 (40343032)
Project Period (FY) 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2004: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2003: ¥3,300,000 (Direct Cost: ¥3,300,000)
Keywordsノックアウトマウス / 情動 / モノアミントランスポーター / オピオイド受容体 / 免疫組織染色 / コカイン / 脳内微少透析法 / ストレス / 脳内自己刺激試験 / ブプレノルフィン / 条件付け場所嗜好性試験 / 脳内微笑透析法
Research Abstract

報酬回路は情動と密接に関係する高次神経回路であり、多くの精神疾患での機能異常が想定されている。報酬回路では中脳皮質辺縁系ドーパミン神経系が中心的な役割を果たしていると考えられていたが、我々は他のモノアミンやオピオイド神経伝達の関与についても検討した。
1.モノアミンの報酬に関する研究
報酬効果に関する脳内モノアミン神経伝達を解析することを目的に脳内微少透析法を用いて検討した。報酬行動の獲得に深く関与する快情動の記憶・学習には、中脳辺縁ドーパミン(DA)系神経伝達に加えてセロトニン(5-HT)神経伝達も関与することを申請者らは見出した。またコカインによる場所嗜好性試験による報酬に対応して細胞外ドーパミン濃度が増加したのは、線状体であることがわかった。コカインの報酬にはドーパミントランスポーター(DAT)だけでなく、セロトニントランスポーター(SERT)が共に関与し、さらに同族トランスポーターの補完作用が存在する可能性を示した。さらに同族トランスポーターの補完作用を示すため免疫組織染色法を用いてDA神経内に5-HTの存在を示した。
2.オピオイドの報酬・意欲に関する研究
オピオイドの報酬効果はミューオピオイド受容体(μOR)を標的分子とすることがミューオピオイド受容体欠損マウス(μOR-KO)の行動解析から、我々は明らかにした。本研究では報酬・意欲に関する脳内オピオイド神経伝達の役割を解析することを目的に検討した。
μオピオイド受容体ノックアウト(MOR-KO)マウスにおいて、テイルサスペンション法と水車法による逃避意欲試験を行い、MOR-KOマウスではストレス負荷による意欲低下に耐性を示すことを示した。

Report

(2 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (64 results)

All 2005 2004 Other

All Journal Article (26 results) Book (4 results) Publications (34 results)

  • [Journal Article] A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia.2005

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

      Neurosci Lett 376(3)

      Pages: 182-187

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 報酬効果と鎮痛効果の異なる作用機序2005

    • Author(s)
      井手聡一郎, 他
    • Journal Title

      日本薬理学雑誌 125

      Pages: 11-15

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Mu opioid receptor knockout mice display reduced cocaine conditioned place preference but enhanced sensitization of cocaine-induced locomotion.2004

    • Author(s)
      Hall FS, et al.
    • Journal Title

      Brain Res Mol Brain Res 121(1-2)

      Pages: 123-130

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Association between the glutathione S-transferase M1 gene deletion and female methamphetamine abusers.2004

    • Author(s)
      Koizumi H, et al.
    • Journal Title

      Am J Med Genet 126B(1)

      Pages: 43-45

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Functional identification of ASCT1 neutral amino acid transporter as the predominant system for the uptake of L-serine in rat neurons in primary culture.2004

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

      Neurosci Res 49(1)

      Pages: 101-111

    • NAID

      10023899113

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Nerve injury induces a tonic bilateral mu-opioid receptor-mediated inhibitory effect on mechanical allodynia in mice.2004

    • Author(s)
      Mansikka H, et al.
    • Journal Title

      Anesthesiology 100(4)

      Pages: 912-921

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Association of neural cell adhesion molecule 1gene polymorphisms with bipolar affective disorder in Japanese individuals.2004

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

      Biol Psychiatry 55(8)

      Pages: 804-810

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Association study of polymorphisms in the 5' upstream region of human DISC1 gene with schizophrenia.2004

    • Author(s)
      Kockelkorn TT, et al.
    • Journal Title

      Neurosci Lett 368(1)

      Pages: 41-45

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.2004

    • Author(s)
      Shen H, et al.
    • Journal Title

      Neuropsychopharmacology 29(10)

      Pages: 1790-1799

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice.2004

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

      Neuropsychopharmacology 29(9)

      Pages: 1656-1663

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Changes in expression of the mouse homologues of KIAA genes after subchronic methamphetamine treatment.2004

    • Author(s)
      Yamamoto H, et al.
    • Journal Title

      Ann New York Acad Sci 1025

      Pages: 92-101

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A possible genetic mechanism underlying individual and interstrain differences in opioid actions : focus on the mu opioid receptor gene.2004

    • Author(s)
      Han W, et al.
    • Journal Title

      Ann New York Acad Sci 1025

      Pages: 370-375

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Gene polymorphisms of the mu opioid receptor in methamphetamine abusers.2004

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

      Ann New York Acad Sci 1025

      Pages: 316-324

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Food-reinforced operant behavior in dopamine transporter knockout mice : enhanced resistance to extinction.2004

    • Author(s)
      Hironaka N, et al.
    • Journal Title

      Ann New York Acad Sci 1025

      Pages: 140-145

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Study of association between alfa-synuclein gene polymorphism and methamphetamine psychosis/dependence.2004

    • Author(s)
      Kobayashi H, et al.
    • Journal Title

      Ann New York Acad Sci 1025

      Pages: 325-334

    • Related Report
      2004 Annual Research Report
  • [Journal Article] A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis.2004

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

      Ann New York Acad Sci 1025

      Pages: 307-315

    • Related Report
      2004 Annual Research Report
  • [Journal Article] No association between the type 1 sigma receptor gene polymorphisms and methamphetamine abuse in the Japanese population : A collaborative study by the Japanese genetics initiative for drug abuse.2004

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

      Ann New York Acad Sci 1025

      Pages: 27-33

    • Related Report
      2004 Annual Research Report
  • [Journal Article] No association between the candidate genes of t-PA/Plasminogen system and Japanese methamphetamine related disorder.2004

    • Author(s)
      Iwata N, et al.
    • Journal Title

      Ann New York Acad Sci 1025

      Pages: 34-38

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain.2004

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

      Ann New York Acad Sci 1025

      Pages: 102-109

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Molecular mechanisms underlying the rewarding effects of cocaine.2004

    • Author(s)
      Hall FS, et al.
    • Journal Title

      Ann New York Acad Sci 1025

      Pages: 47-56

    • Related Report
      2004 Annual Research Report
  • [Journal Article] DNAマイクロアレイを出発点とした統合失調症の病態に関与する遺伝子の研究2004

    • Author(s)
      糸川昌成, 他
    • Journal Title

      精神神経学雑誌 106(1)

      Pages: 42-48

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 覚醒剤の体内動態と脳内分布2004

    • Author(s)
      沼知陽太郎, 他
    • Journal Title

      Clinical Neuroscience 22(6)

      Pages: 693-695

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 遺伝子改変マウスモデルを用いた薬物依存と統合失調症の病態研究2004

    • Author(s)
      曽良一郎, 他
    • Journal Title

      脳と精神の医学 15(3)

      Pages: 311-316

    • Related Report
      2004 Annual Research Report
  • [Journal Article] オピオイド受容体の分子生物学2004

    • Author(s)
      曽良一郎, 他
    • Journal Title

      日本ペインクリニック学会誌 11(4)

      Pages: 406-410

    • NAID

      10012625692

    • Related Report
      2004 Annual Research Report
  • [Journal Article] モノアミン神経伝達と報酬の分子メカニズム2004

    • Author(s)
      曽良一郎, 他
    • Journal Title

      応用薬理 66(3/4)

      Pages: 241-245

    • NAID

      10013777745

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 双極性障害および統合失調症における性差と神経細胞接着分子の関連研究2004

    • Author(s)
      新井誠, 他
    • Journal Title

      脳と神経の医学 15(4)

      Pages: 477-488

    • Related Report
      2004 Annual Research Report
  • [Book] こころの健康科学研究-現状と課題-2004

    • Author(s)
      佐藤光源, 他
    • Total Pages
      14
    • Publisher
      財団法人精神・神経科学振興財団
    • Related Report
      2004 Annual Research Report
  • [Book] オピオイド研究の進歩と展望2004

    • Author(s)
      井手聡一郎, 他
    • Total Pages
      10
    • Publisher
      ネオメディカル
    • Related Report
      2004 Annual Research Report
  • [Book] オピオイド研究の進歩と展望2004

    • Author(s)
      池田和隆, 他
    • Total Pages
      6
    • Publisher
      ネオメディカル
    • Related Report
      2004 Annual Research Report
  • [Book] 精神疾患100の仮説2004

    • Author(s)
      沼知陽太郎, 他
    • Total Pages
      3
    • Publisher
      星和書店
    • Related Report
      2004 Annual Research Report
  • [Publications] Murphy DL, et al.: "Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders."Genes Brain Behav. 2(6). 350-364 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hall FS, et al.: "Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter DAT knockout mice."Neuropsychopharmacology. 128. 620-628 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hall FS, et al.: "Congenic C57BL/6 mu opiate receptor (MOR) knockout mice : baseline and opiate effects."Genes Brain Behav. 2. 114-121 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yuyama K, et al.: "Overexpression of V-1 prevents NO-induced cell death : involvement of enhanced tetrahydrobiopterin (BH_4) biosynthesis."J Neurosci Res. 72(6). 716-725 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yuyama K, et al.: "Caspase-independent cell death by low concentrations of nitric oxide (NO) in PC12 cells : involvement of the inhibition of cytochrome C oxidase and the production of reactive oxygen species (ROS) in mitochondria."J Neurosci Res. 73(3). 351-363 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Itokawa M, et al.: "Association between a novel polumorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans."Neurosci Lett. 347. 202-204 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ujike H, et al.: "Nine-or fewer repeat alleles in VNTR polymorphism of the dopamine transporter gene is a strong risk factor for prolonged methamphetamine psychosis."Pharmacogenomics J. 3(4). 242-247 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizoguchi H, et al.: "Lack of the mu-opioid receptor-mediated G-protein activation in the mouse spinal cord lacking exon1 and exon 2 & 3 of MOR-1 gene."J Pharmacol Sci. 93. 423-429 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shen H, et al.: "Electroconvulsive shock increases serotonin transporter in the rat frontal cortex."Neurosci Lett. 341(2). 170-172 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kabbaj M, et al.: "Methamphetamine differentially regulates hippocampal glucocorticoid and mineralocorticoid receptors mRNAs in Fisher and Lewis rats."Brain Res Mol Brain Res. 117(1). 8-14 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobayashi T, et al.: "Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac)."Br J Pharmacol. 138. 1119-1128 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto T, et al.: "Characterization of rapid and high-affinity uptake of L-serine in neurons and astrocytes in primary culture."FEBS Lett. 548. 69-73 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hall FS, et al.: "Mu opioid receptor knockout mice display reduced cocaine conditioned place preference but enhanced sensitization of cocaine induced locomotion."Brain Res. 121(1-2). 123-130 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto H, et al.: "Changes in expression of the mouse homologues of KIAA genes after subchronic methamphetamine treatment."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Han W, et al.: "A possible genetic mechanism underlying individual and interstrain differences in opioid actions : focus on the mu opioid receptor gene."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ide S, et al.: "Gene polymorphisms of the mu opioid receptor in methamphetamine abusers."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hironaka N, et al.: "Food-reinforced operant behavior in dopamine transporter knockout mice : enhanced resistance to extinction."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobayashi H, et al.: "Association study between alfa-synuclein gene polymorphism and methamphetamine dependence."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Harano M, et al.: "TaqI A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Inada T, et al.: "No association between the type I sigma receptor gene polymorphisms and methamphetamine abuse in the Japanese population : A. collaborative study by the Japanese Genetics Initiative for Drug Abuse (JGIDA)."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwata N, et al.: "No association between the candidate genes of t-PA/Plasminogen system and Japanese methamphetamine related disorder : A collaborative study by the Japanese Genetics Initiative for Drug Abuse (JGIDA)."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Numachi Y, et al.: "Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hall FS, et al.: "The molecular mechanisms underlying the rewarding effects of cocaine."Ann New York Acad Sci. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shen H, et al.: "Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters."Neuropsychopharmacology. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto T, et al.: "Functional identification of ASCT1 neutral amino acid transporter as thepredominant system for the uptake of L-serine in rat neurons in primaryculture."Neurosci Res. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ide S, et al.: "Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice."Neuropsychopharmacology. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mansikka H, et al.: "Nerve injury induces a tonic bilateral : mu-opioid receptor mediated inhibitory effect on mechanical allodynia in mice."Anesthesiology. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 沼知陽太郎, 他: "うつと不安の共通因子"Bulletin of Depression and Anxiety. 1. 8-11 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 増良一郎, 他: "カテコラミントランスポーターと高次神経機能"自律神経. 40. 238-243 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 糸川昌成, 他: "DNAマイクロアレイを出発点とした統合失調症の病態に関与する遺伝子の研究"精神神経学雑誌. 106(1). 42-48 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 沼知陽太郎, 他: "覚醒剤の体内動態と脳内分布"Clinical Neuroscience. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 沼知陽太郎, 他: "ストレス逆耐性仮説"こころの臨床. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sora I, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ikeda K, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2018-03-28  

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