Novel approaches for treatment of addiction after social defeat stress

• Project/Area Number: 18K07401
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Kurume University
• Principal Investigator: Yoshinori Ohnishi 久留米大学, 医学部, 助教 (10626865)
• Co-Investigator(Kenkyū-buntansha): 河原 幸江 久留米大学, 医学部, 准教授 (10279135) ; 西 昭徳 久留米大学, 医学部, 教授 (50228144) ; 大西 陽子 久留米大学, 医学部, 助教 (70727586)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 転写因子 / FosB / AP-1 / コカイン / 依存症 / うつ病 / ストレス / 行動実験 / 酸化ストレス反応 / マウス / AAV / 食事療法

Outline of Final Research Achievements

Cocaine increases the concentration of dopamine released by dopaminergic nerves projecting from the ventral tegmental area to the nucleus accumbens. On the other hand, the frequency of firing of that dopaminergic nerve is increased in depression. Also, when we are stressed, we are more likely to turn to addictive substances, and addictive drugs form a negative spiral that worsens depression. We have identified a molecular mechanism by which stress and cocaine work in concert to exacerbate dependence on addictive drugs, and have found foods and drugs to prevent this. We also found that the presence of p11 in acetylcholinergic interneurons in the nucleus accumbens is essential for cocaine-induced elevation of dopamine release, and that accumulation of DFosB in the ventral hippocampus is important for an anti-stress state in response to stress.

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Academic Significance and Societal Importance of the Research Achievements

我々はコカイン投与のみ、ストレス刺激のみでは誘導されないが、うつ状態でのコカイン投与でのみ上昇する分子を同定しており、それがコカインの繰り返し投与やストレス時に誘導されるDFosBと結合することを見出しました。その標的蛋白質、および遺伝子を同定するためにHA-fosBマウスを製作しました。さらにコカイン刺激、メスと出会ったときの刺激、甘いものを食べたときの刺激で側坐核でドーパミンが上昇するのですが、それが側坐核側の介在神経機能でON/OFFされるメカニズムを明らかにしました。さらにストレスに対して拮抗する状態には側坐核だけでなく、腹側海馬のDFosBが重要であることを明らかにしました。

Research Products

• [Journal Article] Circuit-specific hippocampal ΔFosB underlies resilience to stress-induced social avoidance. (2020)
  • Author(s): 11.Eagle AL, Manning CE, Williams ES, Bastle RM, Gajewski PA, Garrison A, Wirtz AJ, Akguen S, Brandel-Ankrapp K, Endege W, Boyce FM, Ohnishi YN, Mazei-Robison M, Maze I, Neve RL, Robison AJ.
  • Journal Title: Nature Communications Volume: 11(1) Issue: 1 Pages: 4484-4496
  • DOI: 10.1038/s41467-020-17825-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hippocampal Subgranular Zone FosB Expression Is Critical for Neurogenesis and Learning (2019)
  • Author(s): Manning Claire E.、Eagle Andrew L.、Kwiatkowski Christine C.、Achargui Ridouane、Woodworth Hillary、Potter Emily、Ohnishi Yoshinori、Leinninger Gina M.、Robison A.J.
  • Journal Title: Neuroscience Volume: 406 Pages: 225-233
  • DOI: 10.1016/j.neuroscience.2019.03.022
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Obligatory roles of dopamine D1 receptors in the dentate gyrus in antidepressant actions of a selective serotonin reuptake inhibitor, fluoxetine (2018)
  • Author(s): Shuto Takahide、Kuroiwa Mahomi、Sotogaku Naoki、Kawahara Yukie、Oh Yong-Seok、Jang Jin-Hyeok、Shin Chang-Hoon、Ohnishi Yoshinori N.、Hanada Yuuki、Miyakawa Tsuyoshi、Kim Yong、Greengard Paul、Nishi Akinori
  • Journal Title: Molecular Psychiatry Volume: 10 Issue: 6 Pages: 1-16
  • DOI: 10.1038/s41380-018-0316-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p11 in Cholinergic Interneurons of the Nucleus Accumbens Is Essential for Dopamine Responses to Rewarding Stimuli (2018)
  • Author(s): Hanada Y.、Kawahara Y.、Ohnishi Y. N.、Shuto T.、Kuroiwa M.、Sotogaku N.、Greengard P.、Sagi Y.、Nishi A.
  • Journal Title: eneuro Volume: 5 Issue: 5 Pages: 0332-18
  • DOI: 10.1523/eneuro.0332-18.2018
  • NAID: 130007812630
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] お酒の力でモテないオスマウスはメスマウスの興味をひくことができるのか？ (2020)
  • Author(s): 大西克典、河原幸江、大西陽子、西昭徳
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 魅力的なオスマウスの剃毛はメスマウスを惹きつける力を失わせるか？ (2020)
  • Author(s): 大西克典、河原幸江、大西陽子、西昭徳
  • Organizer: 第73回日本薬理学会西南部会
• [Presentation] モテるオスはハゲるとモテなくなるのか？ (2019)
  • Author(s): 大西克典、河原幸江、大西陽子、西 昭徳
  • Organizer: NEURO 2019
• [Presentation] Does baldness of attractive male decrease his external and internal power to fascinate female in mice? (2019)
  • Author(s): Ohnishi YN, Kawahara Y, Ohnishi YH, Nishi A
  • Organizer: Neuroscience 2019
  • Int'l Joint Research
• [Presentation] アルコールを飲むことでメスのオスへの嗜好性やドーパミン反応性はどう変化するか (2019)
  • Author(s): 大西克典、河原幸江、大西陽子、西昭徳
  • Organizer: 第72回日本薬理学会西南部会
• [Presentation] モテるオスの分子神経基盤を探る (2019)
  • Author(s): 大西克典、河原幸江、大西陽子、西昭徳
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] Is it possible that non-attractive male mouse can get attractive mind set? (2018)
  • Author(s): Ohnishi YN, Kawahara Y, Ohnishi YH, Nishi A
  • Organizer: Neuroscience 2018
  • Int'l Joint Research
• [Presentation] モテるオスにはどうしたらなれるのか？ (2018)
  • Author(s): 大西克典、河原幸江、大西陽子、西 昭徳
  • Organizer: 第41回日本分子生物学会年会
• [Remarks]
  • URL: http://www.med.kurume-u.ac.jp/med/pharm/
• [Remarks] eNeuro Research Highlight
  • URL: http://www.eneuro.org/content/6/2/ENEURO.0105-19.2019
• [Remarks] 久留米大学医学部薬理学講座HP
  • URL: http://www.med.kurume-u.ac.jp/med/pharm/