Doral raphe 5-HT neurons mediating estrogenic regulation of binge drinking

The ovarian hormone estrogen promotes binge drinking and contributes to sex differences in alcohol abuse. Interestingly, we found an association between estrogen signaling and the brain serotonin (5-hydroxytryptamine, 5-HT) system, a key modulator of alcohol intake. For example, both estrogen receptor α (ERα) and β (ERβ) are highly expressed in the 5-HT neurons in the dorsal raphe (5-HTDRN), the largest serotonergic neural population and a major source of 5-HT. Notably, chronic binge-like ethanol intake led to sex-specific alterations in mRNA expression of ERα and 5-HT-related genes in the DRN in mice, suggesting a potential role of estrogen/ERs/5- HT signaling in binge drinking. Notably, we found that either ERα or ERβ agonist treatment attenuated the stimulatory effects of alcohol on 5-HTDRN neurons, which may contribute to the higher levels of binge drinking in females. We also showed that chemogenetic activation of ERαDRN or ERβDRN neurons reduced binge drinking in female mice. These results support a model in which estrogen acts on ERα/β to prevent alcohol-induced activation on 5-HTDRN neurons, leading to higher binge alcohol drinking. To test this hypothesis, we will pursue three aims in the current grant. (1) We will test whether ERα and ERβ expressed by 5-HTDRN neurons are required for estrogenic regulation of alcohol binge drinking. (2) We will determine whether estrogen signaling mediates the sex dimorphic response of 5-HTDRN neurons to alcohol excitation. (3) We will determine the 5-HTDRN downstream neural circuit that mediate the stimulatory effects of estrogens on alcohol binge drinking. Thus, the proposed studies will be able to identify the specific receptor, neural population, neuronal firing, and neural circuit mechanisms that mediate estrogens’ stimulatory effects on binge drinking. This proposal will investigate one of the fundamental mechanisms contributing to the sex-dimorphism of excessive drinking. The results will provide novel information for identifying new targets to develop more effective, individualized treatment for binge drinking and alcohol-use disorders.