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

2019 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

薬理学

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。