Ethanol Self-Administration Reduces mGlu2/3 Protein Expression in the Nucleus Accumbens and mGlu2/3 Activation Suppresses Binge Drinking in Male Mice

Abstract

Background

Alcohol use disorder (AUD) is associated with dysregulated glutamatergic signaling within mesocorticolimbic circuits that govern reinforcement and excessive ethanol intake. Group II metabotropic glutamate receptors (mGlu2/3) act primarily as presynaptic autoreceptors that regulate glutamate release. However, how voluntary alcohol intake alters mGlu2/3 expression within reward circuitry remains unclear.

Methods and Results

We examined mGlu2/3 protein expression following a history of voluntary ethanol exposure and operant self-administration and, in separate cohorts, assessed the functional impact of group II receptor modulation on binge-like ethanol intake. Male C57BL/6J mice received two weeks of home-cage access to sweetened ethanol or sucrose followed by 35 days of operant self-administration. Immediately after the final session, tissue punches from the nucleus accumbens (NAc), amygdala, and prefrontal cortex were collected for immunoblot analysis. mGlu2/3 expression was reduced in the NAc of ethanol-exposed mice with no statistically significant changes detected in the amygdala or prefrontal cortex. In separate binge-drinking cohorts, systemic administration of the mGlu2/3 agonist LY379268 reduced binge-like ethanol intake in a limited-access home-cage drinking model, whereas positive allosteric modulation of mGlu2 receptors with LY487379 was ineffective.

Conclusions

Voluntary ethanol self-administration was associated with reduced mGlu2/3 protein expression in the NAc. Systemic pharmacological activation of group II receptors suppressed binge-like ethanol consumption. These findings identify mGlu2/3 dysregulation in a key reward-related brain region as a molecular adaptation associated with voluntary ethanol intake and demonstrate mechanistic regulation of binge drinking. This suggests that group II metabotropic glutamate signaling is a viable therapeutic target for treating AUD.