Ethanol and the Female Brain: Estrogen as a Regulator of Ethanol Reward and Drinking Behavior

Abstract

Recent decades have seen a dramatic increase in the incidence of alcohol use disorder (AUD) among women. Despite the substantial risk that AUD poses to women’s health, however, females remain underrepresented in AUD research, and little information about alcohol’s effects on the female brain is available to guide the development of more effective preventative and treatment measures. A growing body of evidence implicates the ovarian steroid hormone 17β-estradiol (E2) as a regulator of female drinking behavior, but the neurological mechanisms via which E2 regulates alcohol intake are unknown. Here I have demonstrated that E2 enhances the rewarding properties of alcohol (ethanol) in female mice, as measured by the conditioned place preference (CPP) test. This is the first study to demonstrate that estradiol regulates ethanol reward in female mice. To investigate potential neural mechanisms by which E2 may act to enhance ethanol reward and drinking behavior, I have conducted a series of behavioral and molecular tests manipulating the activity or expression of the classical estrogen receptors (ERs), ERα and ERβ, to which E2 binds with approximately equal affinity. First, using ERα- and ERβ-selective agonists, I showed that the classical ERs regulate ethanol CPP in female mice. Notably, my results suggest that activation of both ERα and ERβ is required for estrogenic enhancement of ethanol reward. This finding is complemented by my experiments using the drinking in the dark (DID) test, which models voluntary, binge-like ethanol drinking. Using RNAi-mediated knockdown, I demonstrated that ERα or ERβ in the ventral tegmental area (VTA) contribute to the regulation of ethanol consumption by gonadally intact female mice. Knocking down intra-VTA expression of either classical ER significantly reduced binge-like ethanol intake in females. Importantly, this was a sex-specific effect, because knockdown of either receptor failed to produce a decrease in drinking in male mice. In conclusion, my research builds upon existing studies, supporting the idea that E2 may enhance female vulnerability to AUD by increasing ethanol reward and binge-like drinking. Future research should investigate the potential for sex-specific treatment options, including medications that regulate ovarian hormone production and/or modulate the activity of ERs in the brain.