Striatal fast-spiking interneurons regulate compulsive alcohol consumption

Abstract

Persistent drinking in the face of a negative consequence, or compulsive drinking, is a prominent feature of alcohol use disorder. This behavior is directed, in part, by habitual actions encoded by the dorsolateral striatum, or the putamen in humans and nonhuman primates. How ethanol targets the dorsolateral striatum to drive compulsive drinking is poorly understood. However, parvalbumin-expressing striatal fast-spiking interneurons, which comprise ~1% of the total neuronal striatal population, are enriched in the dorsolateral striatum, regulate habit formation, and are functionally modulated by ethanol. To determine whether fast-spiking interneurons are necessary for compulsive ethanol consumption, we selectively ablated these neurons in adult male and female C57BL/6J mice undergoing a voluntary chronic intermittent ethanol consumption paradigm followed by a compulsive ethanol drinking assay. Fast-spiking interneuron ablation curtailed the development of organized ethanol lick sequence behavior, reduced ethanol consumption, and abrogated compulsive consumption of ethanol with the added bitterant quinine. We subsequently investigated how chronic ethanol exposure modulates the physiology of dorsal striatum fast-spiking interneurons. To this end, we utilized ex vivo whole-cell patch clamp electrophysiology and found that 5-week ethanol vapor exposure specifically reduced GABAergic transmission onto dorsal striatum fast-spiking interneurons. This effect corresponded with a significant reduction in the number of GABAergic synapses that was predominantly seen on the soma and proximal processes of fast-spiking interneurons. Perineuronal nets, a subdivision of the extracellular matrix predominately expressed on parvalbumin-expressing interneurons, condense around the soma and proximal branches to regulate synaptic transmission. We found that 5-week ethanol vapor exposure degraded dorsal striatum perineuronal nets and that enzymatically degrading perineuronal nets reduces GABAergic transmission. Lastly, we investigated how GABAergic transmission responds to acute ethanol in slice and found that acute bath application of ethanol potentiates GABAergic transmission onto fast-spiking interneurons, but that 5-week ethanol vapor exposure prevents acute ethanol potentiation of GABAergic transmission, suggesting that GABAergic inputs onto fast-spiking interneurons undergo a homeostatic adaptation to repeated ethanol exposure. Collectively this work provides a novel insight into the pathophysiology of chronic ethanol exposure and identifies multiple therapeutic substrates for future interventions against compulsive drinking.