Gonadal hormones and sex chromosome complement differentially contribute to ethanol intake, preference, and relapse-like behavior in Four Core Genotypes mice

Alcohol use and high-risk alcohol drinking behaviors among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the Four Core Genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviors. FCG mice were given access to escalating concentrations of EtOH in a two-bottle, 24-h continuous access drinking paradigm to assess consumption and preference. Relapse-like behavior was measured by assessing escalated intake following repeated cycles of deprivation and re-exposure. Twenty-four hour EtOH consumption was greater in mice with ovaries (Sry-), relative to those with testes, and in mice with the XX chromosome complement, relative to those with XY sex chromosomes. EtOH preference was higher in XX vs. XY mice. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). Mice with ovaries (Sry-FCG mice and C57Bl/6J females) were also found to consume more water than mice with testes. These results demonstrate that aspects of EtOH drinking behavior may be independently regulated by sex hormones and chromosomes and inform our understanding of the neurobiological mechanisms which contribute to EtOH dependence in male and female mice. Future investigation of the contribution of sex chromosomes to EtOH drinking behaviors is warranted.