Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, 20892, USA.
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD, 20892, USA.
Neuropsychopharmacology. 2024 Apr;49(5):824-836. doi: 10.1038/s41386-023-01731-z. Epub 2023 Sep 8.
The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson's-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.
从愉悦性饮酒向问题性饮酒的转变是酒精使用障碍的一个标志，仅发生在一部分饮酒者中。这种转变需要纹状体神经元表达的多巴胺 D1 受体（D1R）的突触驱动和活动发生持久变化。导致某些个体易发生转变的易感性的分子机制了解较少。在这里，我们报告帕金森病相关蛋白富亮氨酸重复激酶 2（LRRK2）调节纹状体 D1R 功能，以影响对酒精的行为反应和小鼠过渡到大量、持续饮酒的可能性。特异性从表达 D1R 的神经元中缺失 Lrrk2 基因增强了细胞和突触水平的 D1R 信号传导，并增强了与酒精相关的行为和饮酒。特异性缺失 Lrrk2 的小鼠更容易出现大量饮酒，且饮酒对惩罚不敏感。这些发现确定了 LRRK2 功能在纹状体中促进对大量和持续饮酒的抵抗力的潜在新作用。
