2003 年度実績報告書

情動に関与する神経の可塑的変化とモノアミン神経伝達の分子機構

研究課題

研究課題/領域番号	15016006
研究機関	東北大学
研究代表者	曽良一郎東北大学, 大学院・医学系研究科, 教授 (40322713)
研究分担者	萩野洋子 (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 (40332382) 城戸幹太東北大学, 大学院・歯学系研究科, 助手 (40343032) 沼知陽太郎東北大学, 大学院・医学系研究科, 助教授 (00261636) 吉田寿美子仙台大学, 体育学部, 教授 (50261532) 沈昊偉 (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
キーワード	ノックアウトマウス / 脳内微笑透析法 / コカイン / キノアミントランスポーター / 線条体 / 前頭前野皮質 / シナプス小胞 / エタノール
研究概要	コカインの報酬効果は、いずれかのモノアミントランスポーターが欠損しても他のものが補うと考えられ、複雑な分子機構が予想された。我々はコカインの報酬効果におけるドーパミンとセロトニン神経伝達の相互作用を検討するために、ドーパミントランスポーター(DAT)/セロトニントランスポーター(SERT)ダブルKOマウスを作製した。DAT完全欠損にSERT部分あるいは完全欠損が加わることによりコカインの報酬は消失した結果は、コカイン報酬にはDATとSERTが共に関与し、同族トランスポーターの補完作用が働いていることを示唆している。脳内微少透析法を用いて、モノアミントランスポーターKOマウスにおいてドーパミン、セロトニンの基礎値およびコカイン投与時の変化を計測したところ、線条体ではDATシングルKOマウスにおいてコカイン投与によりドーパミンが上昇したが、DAT/SERTダブルKOマウスでは、その上昇が観察されなかったことから、線条体におけるドーパミンの上昇がコカインの報酬効果と相関し、SERTがドーパミン再取り込みを補完したと考えられた。前頭前野皮質では、DAT/SERTダブルKOマウスにおいてもコカイン投与によりドーパミンが上昇したことから、残存するNETがドーパミン再取り込みを補完したと考えられた。エタノールの報酬効果におけるモノアミンの役割について、細胞膜トランスポーターであるDATおよびシナプス小胞モノアミントランスポーター(VMAT)欠損マウスモデルを用いて検討した。DAT欠損マウス、VMAT欠損マウスのいずれにおいても雄マウスはエタノール消費量が上昇している結果は、ドーパミン神経伝達がエタノールの報酬効果に関与することを示唆している。

研究成果

(32件)

すべてその他

すべて文献書誌 (32件)

[文献書誌] 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)
[文献書誌] Hall FS, et al.: "Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice."Neuropsychopharmacology. 28. 620-628 (2003)
[文献書誌] Hall FS, et al.: "Congenic C57BL/6 mu opiate receptor (MOR) knockout mice : baseline and opiate effects."Genes Brain Behav. 2. 114-121 (2003)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] Mizoguchi H, et al.: "Lack of the mu-opioid receptor-mediated G-protein activation in the mouse spinal cord lacking exon 1 and exon 2 & 3 of MOR-1 gene."J Pharmacol Sci. 93. 423-429 (2003)
[文献書誌] Shen H, et al.: "Electroconvulsive shock increases serotonin transporter in the rat frontal cortex."Neurosci Lett. 341(2). 170-172 (2003)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] Ide S, et al.: "Gene polymorphisms of the mu opioid receptor in methamphetamine abusers."Ann New York Acad Sci. in press. (2004)
[文献書誌] 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)
[文献書誌] Kobayashi H, et al.: "Association study between alfa-synuclein gene polymorphism and methamphetamine dependence."Ann New York Acad Sci. in press. (2004)
[文献書誌] Harano M, et al.: "TaqI A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis."Ann New York Acad Sci. in press. (2004)
[文献書誌] Inada T, et al.: "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 (JGIDA)."Ann New York Acad Sci. in press. (2004)
[文献書誌] 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)
[文献書誌] Numachi Y, et al.: "Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain."Ann New York Acad Sci. in press. (2004)
[文献書誌] Hall FS, et al.: "The molecular mechanisms underlying the rewarding effects of cocaine."Ann New York Acad Sci. in press. (2004)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] Ide S, et al.: "Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice."Neuropsychopharmacology. in press. (2004)
[文献書誌] 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)
[文献書誌] 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)
[文献書誌] 曽良一郎, 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)
[文献書誌] 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)
[文献書誌] 沼知陽太郎, 他: "覚醒剤の体内動熊と脳内分布"Clinical Neuroscience. in press. (2004)
[文献書誌] 沼知陽太郎, 他: "ストレス逆耐性仮説"こころの臨床. in press. (2004)
[文献書誌] Sora I, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)
[文献書誌] Ikeda K, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

2003 年度 実績報告書

情動に関与する神経の可塑的変化とモノアミン神経伝達の分子機構

研究代表者

曽良 一郎 東北大学, 大学院・医学系研究科, 教授 (40322713)

研究成果

[文献書誌] 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)

[文献書誌] Hall FS, et al.: "Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knockout mice."Neuropsychopharmacology. 28. 620-628 (2003)

[文献書誌] Hall FS, et al.: "Congenic C57BL/6 mu opiate receptor (MOR) knockout mice : baseline and opiate effects."Genes Brain Behav. 2. 114-121 (2003)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

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

[文献書誌] Shen H, et al.: "Electroconvulsive shock increases serotonin transporter in the rat frontal cortex."Neurosci Lett. 341(2). 170-172 (2003)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] Ide S, et al.: "Gene polymorphisms of the mu opioid receptor in methamphetamine abusers."Ann New York Acad Sci. in press. (2004)

[文献書誌] 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)

[文献書誌] Kobayashi H, et al.: "Association study between alfa-synuclein gene polymorphism and methamphetamine dependence."Ann New York Acad Sci. in press. (2004)

[文献書誌] Harano M, et al.: "TaqI A polymorphism of DRD2 gene and brain atrophy in methamphetamine psychosis."Ann New York Acad Sci. in press. (2004)

[文献書誌] Inada T, et al.: "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 (JGIDA)."Ann New York Acad Sci. in press. (2004)

[文献書誌] 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)

[文献書誌] Numachi Y, et al.: "Psychostimulant alters expression of DNA methyltransferase mRNA in the rat brain."Ann New York Acad Sci. in press. (2004)

[文献書誌] Hall FS, et al.: "The molecular mechanisms underlying the rewarding effects of cocaine."Ann New York Acad Sci. in press. (2004)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] Ide S, et al.: "Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice."Neuropsychopharmacology. in press. (2004)

[文献書誌] 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)

[文献書誌] 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)

[文献書誌] 曽良一郎, 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)

[文献書誌] 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)

[文献書誌] 沼知陽太郎, 他: "覚醒剤の体内動熊と脳内分布"Clinical Neuroscience. in press. (2004)

[文献書誌] 沼知陽太郎, 他: "ストレス逆耐性仮説"こころの臨床. in press. (2004)

[文献書誌] Sora I, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

[文献書誌] Ikeda K, et al.: "Opioid Research : Methods and Protocols"Zhizhong Z.Pan, Humana Press. 12 (2003)

2003 年度実績報告書

曽良一郎東北大学, 大学院・医学系研究科, 教授 (40322713)