Estradiol enhances ethanol reward in female mice through activation of ERα and ERβ

Alcohol use disorder (AUD) manifests differently in men and women, but little is known about sex differences in the brain's response to ethanol. It is known that the steroid hormone 17β-estradiol (E2) regulates voluntary ethanol consumption in female rodents. However, the role of E2 as a regulator of ethanol reward has not been investigated. In this study, we tested for the effects of E2 and agonists selective for the classical estrogen receptors, ERα and ERβ, on ethanol reward in ovariectomized (OVX) mice using the conditioned place preference (CPP) test. E2 enhanced ethanol CPP and, while specific activation of either receptor alone had no effect, co-activation of ERα and ERβ also enhanced ethanol CPP, suggesting that E2 enhances ethanol reward in female mice through actions at both ERα and ERβ. These results have implications for sex differences in the development of AUD, suggesting that women may find ethanol more rewarding than men because of higher circulating E2 levels.