Nucleus accumbens core chemogenetic excitation in male mice and chemogenetic inhibition in female mice reduced ethanol reward.

Background: Women tend to progress from initial alcohol use to dependence more rapidly than men, a phenomenon known as the "telescoping effect". This suggests different consequences of early alcohol use, which can impact the development of an Alcohol Use Disorder (AUD). Previous evidence demonstrated that nucleus accumbens core (NAcC) chemogenetic manipulations resulted in opposite effects on binge-like drinking [stimulation decreased ethanol intake in C57BL/6J (B6) females, while inhibition decreased intake in males]. In humans, ethanol cue conditioning is linked to the positive subjective effects of alcohol intake and intoxication. We tested the hypothesis that chemogenetic manipulation of NAcC activity alters ethanol reward (measured by conditioned place preference, CPP) in a sex-specific manner.

Methods: In Experiment 1, surgery naïve B6 mice (n = 11-12/sex/treatment) underwent an ethanol CPP protocol and were administered the Designer Receptors Exclusively Activated by Designer Drugs (DREADD) actuator clozapine-N-oxide (CNO, 1 mg/kg) or vehicle prior to ethanol (2 g/kg) conditioning. In Experiment 2, B6 mice underwent surgery to deliver control (mCherry), excitatory (hM3Dq), or inhibitory (hM4Di) DREADDs to the NAcC (n = 8-13/sex/treatment). After recovery, mice underwent ethanol CPP as in Experiment 1. CPP was conducted in a 3-chamber apparatus. Time spent in each chamber was recorded during the pre-test (before conditioning), and the test (after 4 ethanol and 4 saline conditioning sessions). Data were analyzed separately by sex, viral condition, and treatment with a 2-way RM ANOVA [factors: Time (repeated measure), Chamber].

Results: Both surgery naïve (Experiment 1) and mCherry-expressing female and male B6 mice condition similarly to an intoxicating dose of ethanol and CNO did not interfere with ethanol CPP in the absence of DREADDs. Experiment 2 revealed that NAcC chemogenetic stimulation prevented ethanol CPP in males, while NAcC chemogenetic inhibition prevented ethanol CPP in females.

Conclusions: NAcC chemogenetic manipulations alter ethanol reward differently in male and female B6 mice. Together with prior work, we demonstrate that NAcC activity has a sex-specific role during ethanol reward and consumption. Evidence of sex differences in ethanol reward may help future research to uncover the mechanisms underlying the "telescoping effect" and why women have an increased risk for developing an AUD.