Estrogen Signaling in the Dorsal Raphe Regulates Binge-Like Drinking in Mice

Authors

Valeria C Torres Irizarry
Bing Feng
Xiaohua Yang
Nirali Patel
Sarah Schaul
Lucas Ibrahimi
Hui Ye
Pei Luo
Leslie Carrillo-Sáenz
Penghua Lai
Maya Kota
Devin Dixit
Chunmei Wang
Amy W Lasek
Yanlin He
Pingwen Xu

Publication Date

2-27-2024

Journal

Translational Psychiatry

DOI

10.1038/s41398-024-02821-2

PMID

38413577

PMCID

PMC10899193

PubMedCentral® Posted Date

2-27-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Female, Male, Animals, Estrogen Receptor alpha, Dorsal Raphe Nucleus, Estrogen Receptor beta, Binge Drinking, Serotonin, Estrogens, Ethanol, Neuroscience, Physiology

Abstract

Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on 5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HTDRN) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HTDRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17β-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERβ are expressed in 5-HTDRN neurons, whereas ERα agonist depolarizes and ERβ agonist hyperpolarizes 5-HTDRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HTDRN neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs’ inhibitory effects on ethanol-induced burst firing of 5-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERβ-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/β to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.