Loss of mGlu5 receptors from PV inhibitory neurons attenuates sex differences in ethanol and sucrose seeking.

Binge drinking continues to pose major societal and health challenges. Understanding the molecular mechanisms that drive problematic alcohol use is critical for developing novel therapeutics. Parvalbumin-expressing interneurons (PV-INs), a key subpopulation of interneurons within the prefrontal cortex (PFC) and other brain areas, have been implicated in a variety of alcohol-seeking behaviors. Recent work has identified the metabotropic glutamate 5 (mGlu5) receptor as a critical sex-specific regulator of PV-IN activity. Genetic deletion of mGlu5 from PV-INs alters PFC-dependent cognitive behaviors and sex-specifically decreases volitional ethanol intake, but its role in motivated drinking remains unknown. Here, we use operant self-administration to examine how disruption of mGlu5 in PV-INs alters motivated drinking. Under a fixed ratio schedule, PV-mGlu5-/- mice show impairments in the acquisition of ethanol self-administration. By contrast, PV-mGlu5-/- mice readily acquire sucrose self-administration, suggesting a specific deficit to ethanol reinforcement. With sucrose administration, we found that males produced more active nosepokes and consumed more sucrose than females, an effect attenuated in male PV-mGlu5-/- mice. Using a fading procedure, mice were gradually transitioned to respond for 20% ethanol. Following the fade, male wildtypes maintained elevated responding relative to females and to male PV-mGlu5-/- mice. Progressive ratio and quinine adulteration suggest that these sex- and genotype-dependent effects reflect differences in motivation rather than altered taste sensitivity. Finally, we found that PV-mGlu5-/- mice displayed reduced expression of perineuronal nets and PV protein, with a greater disruption in males than females. Together, these data highlight mGlu5 receptors and PV-INs as critical regulators of motivated drinking.