Sex differences in binge-like EtOH drinking, corticotropin-releasing hormone and corticosterone: effects of β-endorphin

Binge drinking is an increasingly common pattern of risky use associated with numerous health problems, including alcohol use disorders. Because low basal plasma levels of beta-endorphin (beta-E) and an increased beta-E response to alcohol are evident in genetically at-risk human populations, this peptide is thought to contribute to the susceptibility for disordered drinking. Animal models suggest that the effect of beta-E on consumption may be sex-dependent. Here, we studied binge-like EtOH consumption in transgenic mice possessing varying levels of beta-E: wild-type controls with 100% of the peptide (beta-E +/+), heterozygous mice constitutively modified to possess 50% of wild-type levels (beta-E +/-) and mice entirely lacking the capacity to synthesize beta-E (-/-). These three genotypes and both sexes were evaluated in a 4-day, two-bottle choice, drinking in the dark paradigm with limited access to 20% EtOH. beta-E deficiency determined sexually divergent patterns of drinking in that beta-E -/- female mice drank more than their wild-type counterparts, an effect not observed in male mice. beta-E -/- female mice also displayed elevated basal anxiety, plasma corticosterone and corticotropin-releasing hormone mRNA in the extended amygdala, and all of these were normalized by EtOH self-administration. These data suggest that a heightened risk for excessive EtOH consumption in female mice is related to the drug's ability to ameliorate an overactive anxiety/stress-like state. Taken together, our study highlights a critical impact of sex on neuropeptide regulation of EtOH consumption.