Cholinergic interneurons in the shell region of the nucleus accumbens regulate binge alcohol consumption: A chemogenetic and genetic lesion study.

Abstract

Binge drinking, characterized by heavy episodic alcohol consumption, poses significant health hazards and increases the likelihood of developing an alcohol use disorder (AUD). Given the growing prevalence of this behavior and its negative consequences, there is a need to explore novel therapeutic targets. Accumulating evidence suggests that cholinergic interneurons (CIN) within the shell region of the nucleus accumbens (NAcSh) play a critical role in reward and addiction. However, their specific involvement in binge alcohol administration remains unclear. We hypothesized that CIN in the NAcSh regulates binge alcohol consumption. To test this hypothesis, we used male ChAT-cre mice expressing Cre-recombinase in cholinergic neurons. We performed chemogenetic manipulation using Designer Receptor Exclusively Activated by Designer Drugs (DREADD) to examine the activity, and genetic ablation of CIN in the NAcSh to examine the amount of alcohol consumed in mice exposed to binge alcohol consumption using the 4-Days Drinking-in-Dark (DID) paradigm. The impact of CIN manipulations in the NAcSh on sucrose self-administration was used to control for taste and caloric effects. Additionally, in a separate group of mice, c-Fos immunofluorescence was employed to verify chemogenetic activation or inhibition. Histological and immunohistochemical techniques were used to verify microinfusion sites, DREADD expression in CINs, and genetic ablation. We found that, while chemogenetic activation of CIN in the NAcSh caused a significant increase in alcohol consumption, chemogenetic inhibition or genetic ablation of CIN significantly reduced the amount of alcohol consumed without affecting sucrose self-administration. The chemogenetic inhibition caused a significant reduction, whereas activation caused a significant increase, in the number of c-Fos-labeled CIN in the NAcSh. Our findings highlight the crucial involvement of CIN in the NAcSh in modulating binge alcohol consumption, suggesting that targeting these neurons could serve to modify alcohol-related behaviors.