Sex differences in alcohol-induced transcriptional changes in the nucleus accumbens depend on sex chromosome complement and gonadal type.

Studying sex differences in alcohol drinking behaviors in rodents can reveal molecular and physiological differences that may be relevant to addiction. Prior work with the Four Core Genotypes (FCG) mouse line suggests that sex chromosome complement and gonadal type contribute to ethanol consumption in male vs. female mice. Here, we confirmed an effect of sex chromosome complement on alcohol intake in Sry+ male mice using an intermittent access two-bottle choice model. Mice consumed 20% ethanol or water for 13 sessions over 4.5 weeks. Three days after drinking, tissue from the nucleus accumbens was collected and analyzed using RNASeq. Robust transcriptional changes were identified in male (XY/Sry+) mice drinking ethanol vs. water but not in females (XX/Sry-). There were also limited effects of gonad type (Sry- vs. Sry+) and sex chromosome complement (XX vs. XY) on differential gene expression, suggesting that neither of these factors serves as the primary driver of the transcriptional response to alcohol. Both alcohol drinking and RNASeq analyses demonstrate that sex chromosome complement and gonad type interact to produce distinct behavioral and molecular profiles in males and females.