2021 Fiscal Year Final Research Report

Pharmacological treatment of depression: development of novel therapeutics targeting the dopamine neuronal system

Research Project

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Project/Area Number	19H03410
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 48030:Pharmacology-related
Research Institution	Kurume University
Principal Investigator	Akinori Nishi 久留米大学, 医学部, 教授 (50228144)
Co-Investigator(Kenkyū-buntansha)	河原幸江久留米大学, 医学部, 准教授 (10279135) 大西克典久留米大学, 医学部, 助教 (10626865) 黒岩真帆美久留米大学, 医学部, 助教 (20585690) 首藤隆秀久留米大学, 医学部, 准教授 (70412541) 外角直樹久留米大学, 医学部, 講師 (60368884)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	治療抵抗性うつ病 / アンヘドニア / 抗うつ薬 / ドパミン
Outline of Final Research Achievements	Functional abnormalities of dopaminergic circuits as well as serotonergic circuits are involved in the pathophysiology of depression. p11, which is known to be related to depressive behaviors, likely contributes to the regulation of dopaminergic circuits, but details of its mechanisms are still elusive. Analyses of dopaminergic functions revealed that p11 expressed in cholinergic neurons plays critical roles in dopamine responses to reward and/or hippocampal stimulation in the nucleus accumbens and prefrontal cortex of mouse brain. HCN2 channels in cholinergic neurons are required for p11 function. In addition, dysfunction of dopaminergic circuits was detected in an acute systemic inflammation model of depression. This study suggests the importance of dopaminergic circuits and their regulation by p11 in the pathophysiology of depression.
Free Research Field	神経精神薬理
Academic Significance and Societal Importance of the Research Achievements	抗うつ薬はセロトニン神経系に作用する薬物（SSRI）が主流であるが、治療抵抗性うつ病やアンヘドニアに有効な新規薬物療法の開発が望まれている。本研究により、ドパミン神経系はうつ病の病態と密接に関わっており、コリン作動性神経に発現するp11がその機能調節において重要な役割を果たしていることを明らかにした。p11を介するドパミン神経回路の調節系はうつ病の治療標的であり、詳細な調節分子メカニズムの解明は治療抵抗性うつ病の新規薬物療法を開発するためにも重要である。