Cassandra G Modrak, Sarah E Holstein, April Kim, Elizabeth G Shannon, Sara Faccidomo, Joyce Besheer, Clyde W Hodge
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.
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.