Pathophysiological mechanisms and therapeutic targets for abnormal habit formation-related obsessive-compulsive symptoms

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16009
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Kyoto University (2021); Kyoto Prefectural University of Medicine (2020)
• Principal Investigator: Asaoka Nozomi 京都大学, 医学研究科, 助教 (90826091)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 強迫性障害 / 線条体 / ドパミンD2受容体 / 活性酸素産生酵素

Outline of Final Research Achievements

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by repeatedly rising concern and repetitive behaviors to get rid of the concern. Its precise pathological mechanisms are still being elucidated. Here, we investigated the involvement of NADPH oxidase 1 (NOX1) in compulsive behavior of OCD model mice. behavioral and electrophysiological analysis showed that NOX1 was necessary for induction of D2 receptor stimulation-induced synaptic plasticity in the striatum of OCD model mice. Acute inhibition of NOX1 significantly reduced OCD-related behaviors. Our study suggests that inhibition of NOX1 may become a novel therapeutic target for OCD.

Free Research Field

神経薬理学

Academic Significance and Societal Importance of the Research Achievements

強迫性障害をはじめ、依存症や摂食障害など、強迫的な行動が問題となる疾患では、ドパミン神経系、特にドパミンD2受容体の異常が示唆されていますが、こうしたドパミン系の異常がどのようなメカニズムで強迫性発現に繋がるのかは明らかとなっていませんでした。本研究は、活性酸素産生酵素であるNOX1由来の活性酸素が、ドパミンD2受容体の下流シグナル変動を引き起こすことで、線条体の興奮性シナプス機能の変化を誘発し、強迫性発現に寄与していることを見出しました。本成果は、強迫性発現の新たな神経メカニズム解明、および治療標的の導出に資するものであると考えられます。