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

ABSTRACT Alcohol use disorder (AUD) is highly prevalent and associated with substantial morbidity and high mortality among substance use disorders. While there are currently three FDA-approved medications for treating AUDs, none specifically target the withdrawal/negative affect stage of AUD, underscoring the need to understand the underlying neurobiology during 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. While previous studies have examined alcohol-related adaptations in prefrontal cortical principal glutamatergic neurons, here we used male and female PV:Ai14, SOM:Ai14 and VIP:Ai14 mice to examine 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 EtOH drinking in male and female mice. We found that alcohol withdrawal increased excitability of prelimbic PV interneurons in males, but decreased excitability in prelimbic VIP interneurons in females. Additionally, alcohol withdrawal reduced GABA release onto PV interneurons in males while increasing glutamate release onto VIP interneurons in females. In SOM interneurons, alcohol withdrawal had no effect on excitability, but decreased glutamate release onto SOM interneurons in males. Together, our studies identified sex-specific alcohol withdrawal-induced synaptic plasticity in three different types of interneurons and could provide insight into the cellular substrates of negative affective states associated with alcohol withdrawal.