Neurotoxic effects of chronic ethanol on cholinergic interneurons in the dorsomedial striatum.

Alcohol use disorder (AUD) has severe adverse health and economic impacts totaling over $240 billion in the U.S. annually. Despite this, FDA approved treatments for AUD are limited, thus, further understanding of the neurobiological mechanisms in AUD is required for new treatments. AUD is associated with deficits in behavioral flexibility that are similarly seen in animal models with depletion of dorsal striatal cholinergic interneurons (CINs). We found that acute ethanol (40 mM) inhibits the firing rate of dorsal striatal CINs, which are the primary source of acetylcholine (ACh) in the dorsal striatum. Using an intensity-based ACh sensing fluorescent reporter (iAChSnFR) in slice photometry recordings, we found that acute ethanol (40 mM) inhibits dorsal striatal ACh release. Accordingly, in vivo fiber photometry with iAChSnFR also showed inhibition of ACh release following acute ethanol (2 g/kg ip). To induce ethanol dependence in mice, we used the chronic intermittent ethanol (CIE) vapor exposure model. Following CIE, we found that CIE-treated mice had a significant depression of ACh release compared to control mice in the dorsomedial but not dorsolateral striatum. Then, we performed stereological cell counts of CINs in CIE and control mice to examine the cause of this ACh deficit and found that CIE mice had a significant decrease in CINs in the dorsomedial but not dorsolateral striatum. In conclusion, our data show that ethanol inhibits dorsal striatal cholinergic signaling in a subregion-specific manner that may contribute to AUD related behaviors.