Roles of GABA receptor subtypes in regulation of aminergic activity in the nucleus accumbens

• Project/Area Number: 17K11858
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Nihon University
• Principal Investigator: SAIGUSA Tadashi 日本大学, 松戸歯学部, 教授 (50277456)
• Co-Investigator(Kenkyū-buntansha): 小菅 康弘 日本大学, 薬学部, 准教授 (70383726)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 麻薬性鎮痛薬 / GABA / オピオイド受容体 / GABAA受容体 / GABAB受容体 / ドパミン / アセチルコリン / オピオイド / 側坐核 / GABA受容体 / ラット / 脳微小透析法 / 薬理学 / 神経科学 / シグナル伝達 / 脳・神経 / 歯学

Outline of Final Research Achievements

The nucleus accumbens (NAc) is a terminal area of mesolimbic dopaminergic neurons and contains a subtype of opioid receptors (-Rs) called δ1 and δ2-Rs which may reduce inhibitory neurotransmission. Reduction in GABAA or GABAB-R-mediated inhibition of accumbal dopamine (DA) release due to these δ-Rs activation should be suppressed by stimulating GABAA or GABAB-Rs. We analyzed the effects of GABAA or GABAB-R ligands on δ1 and δ2-R-mediated accumbal DA efflux in freely moving rats using in vivo microdialysis. It is suggested that (1) reduction in GABAA-R-mediated inhibition of dopaminergic activity is necessary to produce δ2-R-mediated accumbal DA efflux and (2) reduction in GABAB-R-mediated inhibition of dopaminergic activity facilitates δ1 and δ2-R-mediated accumbal DA efflux. The present study also provides in vivo neurochemical evidence that activation of GABAA and GABAB-Rs each reduce cholinergic neural activity without affecting dopaminergic neural activity in the NAc.

Academic Significance and Societal Importance of the Research Achievements

麻薬性鎮痛薬は中脳辺縁系DA神経の起始部の腹側被蓋野に存在するμ受容体を刺激して，投射先の側坐核のDA放出を促進すると考えられてきた。申請者らはこのDA放出は腹側被蓋野のみならず側坐核のμ受容体の刺激とこの受容体が発現したGABA介在神経の抑制も関与することを指摘してきた。本研究は，側坐核のδ受容体が分布するGABA介在神経の抑制も同部位のDA神経活動を促進する可能性を示した点に神経薬理学的な意義がある。また，側坐核でDA神経とACh神経は密接な機能的相互作用を起こすが，GABAAおよびGABAB受容体は側坐核のACh神経活動をDA神経活動は介さずに抑制できることを報告できたことも意義深い。

Research Products

• [Int'l Joint Research] アイルランド王立医科大学(アイルランド)
• [Int'l Joint Research] アイルランド王立医科大学(アイルランド)
• [Int'l Joint Research] Royal College of Surgeons in Ireland(アイルランド)
• [Journal Article] OX2 receptors mediate the inhibitory effects of orexin-A on potassium chloride-induced increases in intracellular calcium ion levels in neurons derived from rat dorsal root ganglion in a chronic pain model. (2020)
  • Author(s): Yamaguchi M, Ishikawa M, Aono Y, Saigusa T
  • Journal Title: Neuropsychopharmacology Reports Volume: 40 Issue: 1 Pages: 30-38
  • DOI: 10.1002/npr2.12094
  • Peer Reviewed / Open Access
• [Journal Article] Stimulation of accumbal GABAB receptors inhibits delta1- and delta2-opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats (2018)
  • Author(s): Yuriko Watanabe, Yuri Aono, Masamichi Komiya, John L Waddington, Tadashi Saigusa
  • Journal Title: European Journal of Pharmacology Volume: 837 Pages: 88-95
  • DOI: 10.1016/j.ejphar.2018.08.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In vivo neurochemical evidence that stimulation of accumbal GABAA and GABAB receptors each reduce acetylcholine efflux without affecting dopamine efflux in the nucleus accumbens of freely moving rats (2018)
  • Author(s): Yuri Aono, Yuriko Watanabe, Manabu Ishikawa, Noboru Kuboyama, John L Waddington, Tadashi Saigusa
  • Journal Title: Synapse Volume: 73 Issue: 4
  • DOI: 10.1002/syn.22081
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stimulation of accumbal GABAA receptors inhibits delta2-, but not delta1-, opioid receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats (2017)
  • Author(s): Yuri Aono, Yuri Kiguchi, Yuriko Watanabe, John L Waddington, Tadashi Saigusa
  • Journal Title: European Journal of Pharmacology Volume: 815 Pages: 18-25
  • DOI: 10.1016/j.ejphar.2017.09.019
  • Peer Reviewed
• [Presentation] Orexin-Aとは異なりorexin受容体拮抗薬のMK-4305のラットの側坐核への局所投与は同部位のドパミン放出を促進する (2020)
  • Author(s): 川島央暉、青野悠里、三枝 禎
  • Organizer: 第93回日本薬理学会年会
• [Presentation] α2受容体系薬物がラットの側坐核のアセチルコリン放出に及ぼす効果 (2020)
  • Author(s): 青野悠里、川島央暉、三枝 禎
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Activation of δ1 and δ2 receptors enhances dopamine efflux in the nucleus accumbens of freely moving rats through neural mechanisms involving different combinations of GABA receptor subtypes (2019)
  • Author(s): Yuri Aono, Yuriko Watanabe, Tadashi Saigusa
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP) Congress
  • Int'l Joint Research
• [Presentation] OX2 receptors mediate orexin-A-induced inhibition of KCl-induced increase in intracellular calcium ion levels in neurons derived from dorsal root ganglion of rats with sciatic nerve ligation (2019)
  • Author(s): Tadashi Saigusa, Yuri Aono, Manabu Ishikawa, Masataka Kimura
  • Organizer: 6th Asian College of Neuropsychopharmacology (AsCNP) Congress
  • Int'l Joint Research
• [Presentation] 無麻酔非拘束ラットの側坐核のGABAAおよびGABAB受容体は同部位のドパミン放出に影響を与えずにアセチルコリン放出を抑制する (2019)
  • Author(s): 青野 悠里、渡邉由梨子、石川 学、木村 全孝、三枝 禎
  • Organizer: 第92回日本薬理学会年会
• [Presentation] Analysis of the roles of μ receptor subtypes in the regulation of acetylcholine and dopamine efflux in the nucleus accumbens of freely moving rats (2018)
  • Author(s): Yuri Aono, Yuriko Watanabe and Tadashi Saigusa
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] Activation of accumbal GABAB receptors inhibits δ1 and δ2 receptor-mediated dopamine efflux in the nucleus accumbens of freely moving rats (2018)
  • Author(s): Tadashi Saigusa, Yuri Aono and Yuriko Watanabe
  • Organizer: The 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] Muscimolが無麻酔非拘束ラットの側坐核の細胞外アセチルコリン量に及ぼす効果 (2017)
  • Author(s): 渡邉由梨子，青野悠里，小宮正道，三枝 禎
  • Organizer: 第137回日本薬理学会関東部会