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Drug discovery research targeting the novel regulation of prefrontal dopaminergic system by the functional interaction between the sigma1 and serotonin1A receptors

Research Project

Project/Area Number 16K08268
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionOsaka University

Principal Investigator

AGO Yukio  大阪大学, 薬学研究科, 准教授 (50403027)

Co-Investigator(Kenkyū-buntansha) 田熊 一敞  大阪大学, 歯学研究科, 教授 (90289025)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywordsシグマ1受容体 / 5-HT1A受容体 / GABAA受容体 / 相互作用 / ドパミン / 大脳皮質前頭前野 / 抗うつ作用 / 抗不安作用 / σ1受容体 / 5-HT1A 受容体 / SH-SY5Y細胞 / PC12細胞 / 細胞内カルシウム / c-Fos / 腹側被蓋野 / 雌選択性試験 / 抗うつ薬 / アンヘドニア / 前頭葉
Outline of Final Research Achievements

This study demonstrates that the functional interaction between the 5-HT1A and sigma1 receptors activates prefrontal dopaminergic system under the conditions of decreased brain GABAA receptor function and the neurochemical effect is linked to the anxiolytic- and antidepressant-like effects. GABAergic deficits cause behavioral and endocrine abnormalities that are associated with psychiatric disorders such as anxiety, depression and schizophrenia. Although the exact mechanisms for the interactions among the 5-HT1A, sigma1 and GABAA receptors are unknown, these receptors are potential targets for the treatment of psychiatric disorders.

Academic Significance and Societal Importance of the Research Achievements

我々は,神経ステロイドの干渉を抑制することで,大脳皮質ドパミン神経機能調節におけるσ1受容体-5-HT1A受容体間の相互作用の存在を見出した.またこの作用には,GABAA受容体の機能変化が密接に関わっていることを明らかにした.本研究の成果は,血中神経ステロイド濃度に応じた抗うつ薬の使い分けや薬剤選択に資する神経化学的基盤を示すものであり,また,神経ステロイドあるいはGABAA受容体機能低下に基づくうつ/不安症状に対して,σ1受容体-5-HT1A受容体の機能的相互作用による前頭葉ドパミン神経の活性化が有効であるといった臨床薬学的・薬物治療学的意義を有するものである.

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (24 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (2 results) Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 6 results,  Acknowledgement Compliant: 3 results) Presentation (9 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (3 results)

  • [Int'l Joint Research] National Institute on Aging(米国)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] National Institute on Aging(米国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] mS-11, a mimetic of the mSin3-binding helix in NRSF, ameliorates social interaction deficits in a prenatal valproic acid-induced autism mouse model.2019

    • Author(s)
      Kawase H, Ago Y, Naito M, Higuchi M, Hara Y, Hasebe S, Tsukada S, Kasai A, Nakazawa T, Mishina T, Kouji H, Takuma K, Hashimoto H.
    • Journal Title

      Pharmacol Biochem Behav.

      Volume: 176 Pages: 1-5

    • DOI

      10.1016/j.pbb.2018.11.003

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] LY341495, an mGluR2/3 Antagonist, Regulates the Immunosuppressive Function of Myeloid-Derived Suppressor Cells and Inhibits Melanoma Tumor Growth2018

    • Author(s)
      Morikawa N, Tachibana M, Ago Y, Goda H, Sakurai F, Mizuguchi H
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 41 Issue: 12 Pages: 1866-1869

    • DOI

      10.1248/bpb.b18-00055

    • NAID

      130007539555

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2018-12-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Repeated social defeat stress impairs attentional set shifting irrespective of social avoidance and increases female preference associated with heightened anxiety2018

    • Author(s)
      Higashida Shu、Nagai Hirotaka、Nakayama Kazuki、Shinohara Ryota、Taniguchi Masayuki、Nagai Midori、Hikida Takatoshi、Yawata Satoshi、Ago Yukio、Kitaoka Shiho、Narumiya Shuh、Furuyashiki Tomoyuki
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 10454-10454

    • DOI

      10.1038/s41598-018-28803-1

    • NAID

      120006501224

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] うつ/不安症状に対するσ1受容体-セロトニン1A受容体の機能的相互作用による治療・創薬戦略.2018

    • Author(s)
      吾郷 由希夫
    • Journal Title

      医薬品医療機器レギュラトリーサイエンス

      Volume: 49 Pages: 550-556

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Psychopharmacology of combined activation of the serotonin1A and σ1 receptors2017

    • Author(s)
      Ago Y, Hasebe S, Hiramatsu N, Hashimoto H, Takuma K, Matsuda T
    • Journal Title

      European Journal of Pharmacology

      Volume: 809 Pages: 172-177

    • DOI

      10.1016/j.ejphar.2017.05.035

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism2017

    • Author(s)
      Hara Y, Ago Y, Higuchi M, Hasebe S, Nakazawa T, Hashimoto H, Matsuda T, Takuma K
    • Journal Title

      Hormones and Behavior

      Volume: 96 Pages: 130-136

    • DOI

      10.1016/j.yhbeh.2017.09.013

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impaired extinction of cued fear memory and abnormal dendritic morphology of the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice2017

    • Author(s)
      Ago Y, Hayata-Takano A, Kawanai T, Yamauchi R, Takeuchi S, Cushman JD, Rajbhandari AK, Fanselow MS, Hashimoto H, Waschek JA
    • Journal Title

      Neurobiology of Learning and Memory

      Volume: 145 Pages: 222-231

    • DOI

      10.1016/j.nlm.2017.10.010

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Anti-anhedonic effect of selective serotonin reuptake inhibitors with affinity for sigma-1 receptors in picrotoxin-treated mice2017

    • Author(s)
      Hasebe S, Ago Y, Watabe Y, Oka S, Hiramatsu N, Tanaka T, Umehara C, Hashimoto H, Takuma K, Matsuda T
    • Journal Title

      British Journal of Pharmacology

      Volume: 174 Issue: 4 Pages: 314-327

    • DOI

      10.1111/bph.13692

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Role of prefrontal serotonergic and dopaminergic systems in encounter-induced hyperactivity in methamphetamine-sensitized mice2016

    • Author(s)
      Tanaka T, Ago Y, Umehara C, Imoto E, Hasebe S, Hashimoto H, Takuma K, Matsuda T.
    • Journal Title

      Int. J. Neuropsychopharmacol.

      Volume: 20 Pages: 410-420

    • DOI

      10.1093/ijnp/pyw115

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Involvement of GABAA receptors in 5-HT1A and σ1 receptor synergism on prefrontal dopaminergic transmission under circulating neurosteroid deficiency2016

    • Author(s)
      Ago Y, Hasebe S, Hiramatsu N, Mori K, Watabe Y, Onaka Y, Hashimoto H, Takuma K, Matsuda T.
    • Journal Title

      Psychopharmacology(Berl)

      Volume: 233(17) Issue: 17 Pages: 3125-3134

    • DOI

      10.1007/s00213-016-4353-3

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 動物モデルを用いた精神疾患の病態メカニズム解析と創薬基盤研究2019

    • Author(s)
      吾郷 由希夫
    • Organizer
      一般社団法人予防薬理学研究所キックオフシンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ブチリルコリンエステラーゼ阻害剤は内因性グレリンシグナルを促進して認知機能障害を改善する:ムスカリンM1受容体との機能的相互作用の関与.2018

    • Author(s)
      塚田 信司, 東野 功典, 国本 寿美子, Nigel H. Greig, 橋本 均, 中川 晋作, 吾郷 由希夫
    • Organizer
      第24回創剤フォーラム若手研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Inhibition of butyrylcholinesterase improves prepulse inhibition deficits and enhances M1 muscarinic acetylcholine receptor-mediated responses via ghrelin signaling in mice.2018

    • Author(s)
      Tsukada S, Higashino K, Kunimoto S, Greig NH, Matsuda T, Hashimoto H, Ago Y
    • Organizer
      The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] メタンフェタミン退薬時の社会的刺激による多動反応と前頭前野セロトニン、ドパミン神経系の活性化2017

    • Author(s)
      梅原千晶, 吾郷由希夫, 田中辰典, 長谷部 茂, 橋本 均, 田熊一敞, 松田敏夫
    • Organizer
      第90回日本薬理学会年会
    • Place of Presentation
      長崎パブリックホール
    • Year and Date
      2017-03-15
    • Related Report
      2016 Research-status Report
  • [Presentation] ブチリルコリンエステラーゼ阻害によるグレリンシグナルの活性化を介した中枢ムスカリンM1受容体機能の亢進2017

    • Author(s)
      吾郷由希夫, 東野功典, 国本寿美子, 塚田信司, Nigel H. Greig, 松田敏夫, 橋本 均
    • Organizer
      第14回GPCR研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] Selective serotonin reuptake inhibitors with affinity for σ1 receptors exert anti-anhedonic effect in picrotoxin-induced model of anxiety/depression2017

    • Author(s)
      吾郷由希夫, 長谷部 茂, 樋口桃子, 橋本 均, 田熊一敞, 松田敏夫
    • Organizer
      第60回日本神経化学会大会
    • Related Report
      2017 Research-status Report
  • [Presentation] ブチリルコリンエステラーゼ阻害によるプレパルスインヒビション障害の改善:グレリンシグナルを介したムスカリンM1受容体機能亢進の関与2017

    • Author(s)
      吾郷由希夫, 東野功典, 国本寿美子, 塚田信司, Nigel Greig, 松田敏夫, 橋本 均
    • Organizer
      第39回日本生物学的精神医学会・第47回日本神経精神薬理学会 合同年会
    • Related Report
      2017 Research-status Report
  • [Presentation] 雌性マウスを用いた意欲・報酬探索行動評価試験2016

    • Author(s)
      川瀬啓生, 吾郷由希夫, 長谷部 茂, 岡 智史, 田熊一敞, 松田敏夫, 橋本 均
    • Organizer
      第129回日本薬理学会近畿部会
    • Place of Presentation
      広島県医師会館
    • Year and Date
      2016-06-24
    • Related Report
      2016 Research-status Report
  • [Presentation] 精神的ストレスによる覚せい剤精神病の再燃現象におけるセロトニン受容体の関与2016

    • Author(s)
      田中辰典, 吾郷由希夫, 梅原千晶, 長谷部 茂, 橋本 均, 田熊一敞, 松田敏夫
    • Organizer
      第13回GPCR研究会
    • Place of Presentation
      日本科学未来館
    • Year and Date
      2016-05-13
    • Related Report
      2016 Research-status Report
  • [Remarks] 大阪大学 大学院薬学研究科 薬剤学分野 ホームページ

    • URL

      http://www.phs.osaka-u.ac.jp/homepage/b011/

    • Related Report
      2018 Annual Research Report
  • [Remarks] 大阪大学大学院薬学研究科神経薬理学分野ホームページ

    • URL

      http://molpharm.umin.jp/

    • Related Report
      2017 Research-status Report
  • [Remarks] 大阪大学大学院薬学研究科 神経薬理学分野ホームページ

    • URL

      http://molpharm.umin.jp/

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2022-02-21  

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