Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks.

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Alcohol use disorder (AUD) presents significant challenges in treatment and prevention.
• The G protein-coupled receptor 88 (GPR88) is found in brain regions crucial for reward and addiction.
• Previous studies indicated Gpr88 knockout mice exhibit hyperactivity and risk-taking, but its role in alcohol abuse was unexplored.

Purpose of the Study:

• To investigate the role of GPR88 in alcohol consumption and seeking behaviors.
• To analyze the impact of Gpr88 deletion on brain functional connectivity related to alcohol use.

Main Methods:

• Gpr88 knockout mice were assessed for alcohol drinking and seeking behaviors.
• Resting-state functional magnetic resonance imaging (fMRI) was used to analyze whole-brain functional connectivity in naïve mice.

Main Results:

• Gpr88 knockout mice exhibited increased voluntary alcohol intake and motivation for alcohol.
• Despite increased drinking, alcohol-induced dopamine release and reward were reduced in mutant mice.
• fMRI revealed significant alterations in functional connectivity within mesocorticolimbic pathways, particularly weakened connections involving the prefrontal cortex, ventral tegmental area, and amygdala.

Conclusions:

• GPR88 deletion alters executive, reward, and emotional networks, leading to reduced alcohol reward but increased alcohol seeking and drinking.
• The observed functional connectivity changes resemble those in individuals at risk for AUD.
• GPR88 may serve as a vulnerability or resilience factor for AUD and represents a potential therapeutic target.