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Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

ABSTRACT: The sex steroid hormone estrogen is a key modulator of numerous physiological processes and adaptive behaviors, but it may also be co-opted to drive maladaptive behaviors. While many behavioral roles for estrogen signaling have been shown to occur through canonical genomic signaling mechanisms via nuclear receptors, estrogen can also act in a neurotransmitter-like fashion at membrane-associated estrogen receptors to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high circulating estrogen but a causal role for estrogen in alcohol drinking has not been established. Here, we demonstrate that gonadally intact female mice consume more alcohol and display an anxiolytic phenotype when they have elevated levels of ovarian-derived estrogen across the estrous cycle. We found that rapid, nongenomic estrogen signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis (BNST) is necessary and sufficient for the pro-alcohol drinking effects of ovarian estrogen signaling, regardless of the transcriptional program of a high ovarian estrogen state. We further show that a population of corticotropin-releasing factor (CRF) BNST neurons (BNST^CRF) is a critical mediator of these effects, as high estrogen rapidly enhances synaptic excitation of BNST^CRF neurons and promotes their role in driving binge alcohol drinking. These findings show a causal role for endogenous, ovarian-derived estrogen in hormonal modulation of risky alcohol consumption and provide the first demonstration of a purely rapid, nongenomic signaling mechanism of ovarian estrogen in the brain controlling behavior in gonadally intact females.

SUBMITTER: Zallar LJ

PROVIDER: S-EPMC10635092 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

Zallar Lia J LJ Rivera-Irizarry Jean K JK Hamor Peter U PU Pigulevskiy Irena I Rico Rozo Ana-Sofia AS Mehanna Hajar H Liu Dezhi D Welday Jacqueline P JP Bender Rebecca R Asfouri Joseph J JJ Levine Olivia B OB Skelly Mary Jane MJ Hadley Colleen K CK Fecteau Kristopher M KM Nelson Scottie S Miller John J Ghazal Pasha P Bellotti Peter P Singh Ashna A Hollmer Lauren V LV Erikson David W DW Geri Jacob J Pleil Kristen E KE

bioRxiv : the preprint server for biology 20240815

Ovarian-derived estrogen is a key modulator of numerous physiological processes via genomic and nongenomic mechanisms, including signaling non-canonically at membrane-associated estrogen receptors in the brain to rapidly regulate neuronal function. However, the mechanisms mediating estrogen regulation of behaviors such as alcohol consumption remain unclear. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high c ...[more]

PMID: 37961707

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Project description:ImportanceAlcohol is the most common drug among youth and a major contributor to morbidity and mortality worldwide. Billions of dollars are spent annually marketing alcohol.ObjectiveTo examine the reach of television alcohol advertising and its effect on drinking among underage youth.Design, setting, and participantsLongitudinal telephone- and web-based surveys conducted in 2011 and 2013 involving 2541 US adolescents 15 to 23 years of age at baseline, with 1596 of these adolescents completing the follow-up survey. Cued recall of television advertising images for top beer and distilled spirits brands that aired nationally in 2010-2011 (n = 351). Images were digitally edited to remove branding, and the respondents were queried about 20 randomly selected images. An alcohol advertising receptivity score was derived (1 point each for having seen the ad and for liking it, and 2 points for correct brand identification). Fast-food ads that aired nationally in 2010-2011 (n = 535) were similarly queried to evaluate message specificity.Main outcomes and measuresAmong the underage youth at baseline, we determined (1) the onset of drinking among those who never drank, (2) the onset of binge drinking among those who were never binge drinkers, and (3) the onset of hazardous drinking among those with an Alcohol Use Disorders Identification Test consumption subscore of less than 4. Multivariate regressions were used to predict each outcome, controlling for covariates (demographics, drinking among friends and parents, and sensation seeking), weighting to the US population, and using multiple imputation to address loss to follow-up.ResultsUnderage participants were only slightly less likely than participants of legal drinking age to have seen alcohol ads (the mean percentage of ads seen were 23.4%, 22.7%, and 25.6%, respectively, for youth 15-17, 18-20, and 21-23 years of age; P < .005). The transition to binge and hazardous drinking occurred for 29% and 18% of youth 15 to 17 years of age and for 29% and 19% of youth 18 to 20 years years of age, respectively. Among underage participants, the alcohol advertising receptivity score independently predicted the onset of drinking (adjusted odds ratio [AOR], 1.69 [95% CI, 1.17-2.44]), the onset of binge drinking (AOR, 1.38 [95% CI, 1.08-1.77]), and the onset of hazardous drinking (AOR, 1.49 [95% CI, 1.19-1.86]). Fast-food advertising receptivity was not associated with any drinking outcome.Conclusions and relevanceReceptivity to television alcohol advertising predicted the transition to multiple drinking outcomes. The findings are consistent with the idea that marketing self-regulation has failed to keep television alcohol advertising from reaching large numbers of underage persons and affecting their drinking patterns.

Project description:BackgroundAlcohol dependence (AD) is a complex disorder characterized by impaired control over drinking. It is determined by both genetic and environmental factors. The recent approach of genome-wide association study (GWAS) is a powerful tool for identifying complex disease-associated susceptibility alleles, however, a few GWASs have been conducted for AD, and their results are largely inconsistent. The present study aimed to screen the loci associated with alcohol-related phenotypes using GWAS technology.MethodsA genome-wide association study with the behavior of regular alcohol drinking and alcohol consumption was performed to identify susceptibility genes associated with AD, using the Affymetrix 500K SNP array in an initial sample consisting of 904 unrelated Caucasian subjects. Then, the initial results in GWAS were replicated in three independent samples: 1972 Caucasians in 593 nuclear families, 761 unrelated Caucasian subjects, and 2955 unrelated Chinese Hans.ResultsSeveral genes were associated with the alcohol-related phenotypes at the genome-wide significance level, with the ankyrin repeat domain 7 gene (ANKRD7) showing the strongest statistical evidence for regular alcohol drinking and suggestive statistical evidence for alcohol consumption. In addition, certain haplotypes within the ANKRD7 and cytokine-like1 (CYTL1) genes were significantly associated with regular drinking behavior, such as one ANKRD7 block composed of the SNPs rs6466686-rs4295599-rs12531086 (P = 6.51 × 10(-8)). The association of alcohol consumption was successfully replicated with rs4295599 in ANKRD7 gene in independent Caucasian nuclear families and independent unrelated Chinese Hans, and with rs16836497 in CYTL1 gene in independent unrelated Caucasians. Meta-analyses based on both the GWAS and replication samples further supported the observed significant associations between the ANKRD7 or CYTL1 gene and alcohol consumption.ConclusionThe evidence suggests that ANKRD7 and CYTL1 genes may play an important role in the variance in AD risk.

Dataset Information

Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

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Rapid nongenomic estrogen signaling controls alcohol drinking behavior.

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