Leucine-Rich Repeat Kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking

Abstract

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 is known to require 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. Deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiates D1R signaling at the cellular and synaptic level, enhancing alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 are more prone to heavy alcohol drinking and consumption is insensitive to punishment. These findings identify a novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.

Animal model for high consumption and preference of ethanol and its interplay with high sugar and butter diet, behavior, and neuroimmune system

“…In our results, we observed several genes differentially transcribed in the LRRK2 pathway, including the main one in this pathway, Lrrk2 . In our results, we observed several genes differentially transcribed in the LRRK2 pathway, including Lrrk2 the main one in this pathway ( 31 , 34 – 38 ). This gene produces an kinase anchoring protein (AKAP) that modulates the activity of protein kinase A (PKA), which is involved in the regulation of dopamine receptors ( Drd1 and Drd2 ) transcripts in neurons that project to the striatum in the reward system leading to ethanol preference ( 31 , 34 – 38 ).…”

“…In our results, we observed several genes differentially transcribed in the LRRK2 pathway, including Lrrk2 the main one in this pathway ( 31 , 34 – 38 ). This gene produces an kinase anchoring protein (AKAP) that modulates the activity of protein kinase A (PKA), which is involved in the regulation of dopamine receptors ( Drd1 and Drd2 ) transcripts in neurons that project to the striatum in the reward system leading to ethanol preference ( 31 , 34 – 38 ). In addition, it is known that the Lrrk2 gene is related to the immune system and is biochemically associated with molecular pathways that regulate inflammation, autophagy, and phagocytosis.…”