薬物依存に関係する新しいタンパクの生理機能の解明

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19659017
• Research Category: Grant-in-Aid for Exploratory Research
• Research Institution: Meijo University
• Principal Investigator: 鍋島 俊隆 Meijo University, 薬学部, 教授 (70076751)
• Co-Investigator(Kenkyū-buntansha): 新田 淳美 名古屋大学, 医学部付属病院, 准教授 (20275093)
• Keywords: 遺伝子 / 神経科学 / 生体分子

Research Abstract

薬物依存の形成に寄与すると考えられるいくつかの遺伝子が報告されている。薬物依存の形成は多くのファクターが複雑に絡み合い、未知の遺伝子が関与している可能性も高い。我々はcDNAサブトラクション法を用いて覚せい剤であるメタンフェタミンを連続投与したマウス脳において、2つの新規遺伝子ピッコロとshatiを見出した。平成18年度に行った遺伝子配列にもとづいて作成したアンチセンスヌクレオチドを脳に注入してタンパクの発現を減少させたマウスの実験では、いずれも覚せい剤による場所嗜好性や自発運動の亢進作用を増強したことにより、これらの遺伝子は薬物依存形成を抑制することを報告している。さらにこれらは、ドパミントランスポーターの機能を著しく低下させることも見出した。19年度はこれらの遺伝子を過剰発現させたマウスの作成に着手した。マウスを作成するにあたっては、胎生期のマウス脳で遺伝子が過剰発現するシステムを用いた。それぞれの遺伝子ごとに約10系統の繁殖をはじめており、胎児期での発現量が高いマウスを系統的に選びだし、現在は選択した系統のマウスを用いて、場所嗜好性や行動量測定などの行動薬理学的な実験の計画を立てている。ピッコロについては神経伝達物質の遊離に深く関わっていることが示唆されていることから、過剰発現マウスにおけるアセチルコリン、ドパミン、グルタミン酸などの遊離量をin vivoマイクロダイアイリシス法で検討し、神経障害への関与について検討する予定である

Research Products

• [Journal Article] Transient drug-primed but persistent cue-induced reinstatement of extinguished methamphetamine-seeking behavior in mice. (2007)
  • Author(s): Yan, Y., Yamada, K., Nitta, A. and Nabeshima, T.
  • Journal Title: Behav. Brain Res. 177 Pages: 261-268
  • Peer Reviewed
• [Journal Article] Involvement of glial cell-line derived neurotrophic factor inhibitory effects of a hydorophobic dipeptide Leu-Ile on morphine-induced sensitization and rewarding effects. (2007)
  • Author(s): Niwa, M., Nitta, A., Shen, L., Noda, Y. and Nabeshima, T.
  • Journal Title: Behav. Brain Res., 179 Pages: 167-171
  • Peer Reviewed
• [Journal Article] An inducer for glial cell line-derived neurotrophic factor and tumor necrosis factor-α protects against methamphetamine-induced rewarding effects and sensitization. (2007)
  • Author(s): Niwa, M., Nitta, A., Yamada, Y., Nakajima, A., Saito, K., Seishima, M., Shen, L., Noda, Y., Furukawa, S. and Nabeshima, T
  • Journal Title: Biol. Psychiatry 61 Pages: 890-901
  • Peer Reviewed
• [Journal Article] Tumor Necrosis Factor-alpha and Its Inducer Inhibit Morphine-Induced Rewarding Effects and Sensitization. (2007)
  • Author(s): Niwa, M., A. Nitta, Yamada Y, Nakajima A, Saito K, Seishima M, Noda Y, Nabeshima T.
  • Journal Title: Biol. Psychiatry 62 Pages: 658-668
  • Peer Reviewed
• [Journal Article] Enduring vulnerability to reinstatement of methamphetamine-seeking behavior in glial cell line-derived neurotrophic factor mutant mice. (2007)
  • Author(s): Yan, Y., Yamada, K., Niwa, M., Nagai, T., Nitta, A. and Nabeshima, T
  • Journal Title: FASEB J. 21 Pages: 1994-2004
  • Peer Reviewed
• [Journal Article] A novel molecule 'shati' is involved in methamphetamine-induced hyperlocomotion, sensitization, and conditioned place preference. (2007)
  • Author(s): Niwa, M., Nitta, A., Mizoguchi, H., Ito, Y., Noda, Y., Nagai, T. and Nabeshima, T.
  • Journal Title: J. Neurosci., 27 Pages: 7604-7615
  • Peer Reviewed
• [Journal Article] Reinforcing effects of morphine are reduced in tissue plasminogen activator(tPA)-knockout mice. (2007)
  • Author(s): Yan, Y., Yamada, K., Mizoguchi, H., Noda, Y., Nagai, T., Nitta, A. and Nabeshima, T.
  • Journal Title: Neuroscience 146 Pages: 50-59
  • Peer Reviewed
• [Journal Article] Repeated methamphetamine treatment impairs spatial working memory in rats:reversal by clozapine but not haloperidol. (2007)
  • Author(s): Nagai, T., Takuma, K., Dohniwa, M., Ibi, D., Mizoguchi, H., Kamei, H., Nabeshima, T. and Yamada, K.
  • Journal Title: Psychopharmacology(Berl.) 194 Pages: 21-32
  • Peer Reviewed
• [Presentation] 新規機能分子"shati"はメタンフェタミン依存形成に関与する (2008)
  • Author(s): 丹羽 美苗、新田 淳美、溝口 博之、伊藤 康友、野田 幸裕、永井 拓、鍋島 俊隆
  • Organizer: 第81回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20080317-19
• [Presentation] Tumor necrosis factor-α and its inducer inhibit drug-induced dependence. (2007)
  • Author(s): Nabeshima, T., Niwa, M., Yamada, K., Saito, K., Seishima, M., Noda, Y. and Nitta, A.
  • Organizer: 69th Annual Meeting of College on Problems of Drug Dependence
  • Place of Presentation: Quebec City, Canada
  • Year and Date: 20070616-21
• [Presentation] The blocking mechanisms of Leu-I le against methamphetamine and morphine dependence in mice. (2007)
  • Author(s): Nitta, A., Cen, X., Niwa, M., Ohya, Y., Yamada, Y., Nakajima, A., Saito, K., Seishima, M., Shen, L., Suzuki, M., Saito, K., Noda, Y., Furukawa, S. and Nabeshima, T.
  • Organizer: 69th Annual Meeting of College on Problems of DrugDependence
  • Place of Presentation: Quebec City, Canada
  • Year and Date: 20070616-21
• [Presentation] Tissue plasminogen activator-plasmin-protease activated receptor 1 system regulates rewarding effect of nicotine (2007)
  • Author(s): Nagai, T., Ito, M., Nakamichi, M., Kamei, H., Fukakusa, A., Nabeshima, T., Takuma, K. and Yamada, K.
  • Organizer: 69th Annual Meeting of College on Problems of Drug Dependence
  • Place of Presentation: Quebec City, Canada
  • Year and Date: 20070616-21
• [Presentation] Involvement of a novel molecular "shati" in methamphetamine-induced hyperlocomotion, sensitization and conditioned place preference (2007)
  • Author(s): Nabeshima T.(Invited lecture)Niwa M. Nitta A. Mizoguchi H. Ito Y. Noda Y. Nagai T.'
  • Organizer: A Memorial Event for the 60th Anniversary of Founding of Kangwon National University
  • Place of Presentation: Chunchon, Korea
  • Year and Date: 2007-10-25
• [Presentation] The role of tissue plasminogen active in methamphetamine-induced reward, behavioral sensitization and cognitive deficit in mice. (2007)
  • Author(s): Yamada K. Mizoguchi H., Takuma K., Nabeshima T., and H-C, Kim.
  • Organizer: A Memorial Event for the 60th Anniversary of Founding of Kangwon National University
  • Place of Presentation: Chunchon, Korea
  • Year and Date: 2007-10-25
• [Presentation] Enduring vulnerability to reinstatement of Methamphetamine-seeking behavior in GDNF mutant mice. (2007)
  • Author(s): Nabeshima T. and Yan Y.
  • Organizer: 7th IBRO
  • Place of Presentation: Melborne,
  • Year and Date: 2007-06-16
• [Presentation] Enduring vulnerability to reinstatement of methamphetamine-seeking behavior in glial cell line-derived neurotrophic factor mutant mice. (2007)
  • Author(s): Yan, Y., Yamada, K., Niwa, M., Nagai, T., Nitta A. and Nabeshima T
  • Organizer: 第111回日本薬理学会近畿部会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-06-15