Alcohol Withdrawal Alters the Inhibitory Landscape of the Prelimbic Cortex in an Interneuron- and Sex-specific Manner

Alcohol use disorder (AUD) is highly prevalent and associated with substantial morbidity and mortality. While there are currently three FDA-approved medications for AUD, none specifically target the withdrawal/negative affect stage of AUD, underscoring the need to understand the underlying neurobiological adaptations associated with this critical stage of the addiction cycle. One key region involved in alcohol withdrawal and negative affect is the prelimbic cortex, a subregion of the medial prefrontal cortex. In the present study, we used male and female PV, SOM, and VIP reporter mice to examine cellular and synaptic adaptations in all three major classes of prelimbic cortex interneurons following 72-hour withdrawal from a continuous-access to two-bottle choice model of alcohol. We found that alcohol withdrawal increased PV interneuron excitability in the male cohort but reduced it in the female cohort. In SOM interneurons, withdrawal increased the action potential threshold in males, whereas in VIP interneurons it hyperpolarized the resting membrane potential and reduced membrane resistance in females. Withdrawal also altered synaptic transmission: it enhanced glutamate release onto SOM and VIP interneurons in males but reduced glutamate release onto SOM interneurons in females, and it decreased GABA release onto PV interneurons in males. Together, these findings reveal alcohol withdrawal–induced adaptations in both intrinsic properties and synaptic inputs across prelimbic interneurons, with several patterns differing across the male and female cohorts studied.