2018 Fiscal Year Final Research Report

Development of novel therapeutic approaches focused on phosphodiesterases for psychiatric disorders

Research Project

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Project/Area Number	16K10198
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Psychiatric science
Research Institution	Kurume University
Principal Investigator	Kuroiwa Mahomi 久留米大学, 医学部, 助教 (20585690)
Co-Investigator(Kenkyū-buntansha)	西昭徳久留米大学, 医学部, 教授 (50228144) 首藤隆秀久留米大学, 医学部, 講師 (70412541) 大西克典久留米大学, 医学部, 助教 (10626865)
Research Collaborator	Hikida Takatoshi
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	ホスホジエステラーゼ / ドーパミン / うつ病
Outline of Final Research Achievements	Depression is one of the most common psychiatric disorders, but the etiology of depression is not fully understood. To address the role of adolescent stress in the development of depression, we combined a transgenic mouse model in which a mutation of DISC1, used as a genetic risk factor and adolescent social isolation stress. Both DISC1-mutant mice and wild-type mice with social isolation stress showed depression-like behaviors and showed modest differences in dopamine D1 receptor signaling in the prefrontal cortex and hippocampal dentate gyrus. In addition, in the wild-type mice with environmental enrichment showed enhanced effects of the PDE4 inhibitor rolipram on PKA signaling in the dentate gyrus, however, wild-type mice with social isolation stress showed attenuation of the effects of rolipram. These results suggest that the mutation of DISC1 and social isolation stress may contribute to the development of depression.
Free Research Field	中枢薬理
Academic Significance and Societal Importance of the Research Achievements	個別飼育ストレスを負荷したDISC1遺伝子改変マウスは、遺伝因子と思春期の環境因子の相乗作用が発症要因であるとするtwo-hit-theory に合致した有用な動物モデルである。本研究の結果より、うつ病の発症には遺伝的素因とストレスの負荷が関与していることが示唆され、うつ病のメカニズム解明の糸口となることが期待される。また、うつ病モデル動物を用いた研究およびストレス負荷を行う研究においては、対照群を含め、環境エンリッチメントを始めとする飼育環境の条件設定を厳密に行う必要があることが明らかとなった。