Cholinergic mu-opioid receptor deletion alters reward preference and aversion-resistance

Abstract

Heavy alcohol use and binge drinking are important contributors to alcohol use disorder (AUD). The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT-Cre/Oprm1fl/fl) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms. Male and female ChAT-Cre/Oprm1fl/flmice were generated and heterozygous Cre+ (knockout) and Cre-(control) mice were tested for alcohol and nicotine consumption. In Experiment 1, binge-like and quinine-resistant drinking was tested using 15% ethanol (EtOH) in a two-bottle, limited-access Drinking in the Dark paradigm. Experiment 2 involved a six-week intermittent access paradigm in which mice received 20% EtOH, nicotine, and then a combination of the two drugs. Deleting MORs in cholinergic cells did not alter consumption of EtOH in Experiment 1 or 2. In Experiment 1, the MOR deletion resulted in greater consumption of quinine-adulterated EtOH in male Cre+ mice (vs. Cre-). In Experiment 2, Cre+ mice demonstrated a significantly lower preference for nicotine but did not differ from Cre-mice in nicotine or nicotine + EtOH consumption. These data suggest that cholinergic MORs are involved in nicotine, but not EtOH, drinking behaviors and may contribute to aversion resistant EtOH drinking in a sex-dependent manner.