Binge Drinking Alters Brain Gene Expression Differently in Males and Females

Summary: A new study shows repeated binge drinking produces distinct changes in gene expression in a brain region tied to addiction. Female mice show altered gene activity linked to hormone signaling and immune function, while male mice exhibit changes primarily in genes related to nerve signaling.

Source: Frontiers

Key finding: Repeated binge drinking drives sex-specific changes in gene expression within the nucleus accumbens, a brain region central to reward and addiction. The study found that females and males activate different molecular pathways after repeated binge sessions, underscoring the need for sex-specific approaches to treating alcohol use disorder.

Researchers led by Deborah Finn, Professor of Behavioral Neuroscience at Oregon Health & Science University and Research Pharmacologist at the VA Portland Health Care System, examined how repeated binge ethanol drinking alters molecular pathways in the nucleus accumbens (NAc). The nucleus accumbens plays a critical role in addiction-related behaviors, and understanding sex differences in its molecular response to alcohol can inform targeted therapies.

“We show that repeated binge drinking significantly alters molecular pathways in the nucleus accumbens,” says Finn. “Comparing activated pathways between males and females revealed distinct responses, consistent with other reports showing sex differences after chronic alcohol exposure and withdrawal.”

The research team analyzed the expression of 384 genes previously linked to addiction and mood disorders using a focused qPCR array. The binge protocol involved seven ethanol drinking sessions that produced high intake (average >2.2 g/kg in 30 minutes) and elevated blood ethanol concentrations (average >1.3 mg/ml). Brain tissue was collected 24 hours after the seventh binge session, and gene expression in the NAc was quantified.

Results showed significant sex-dependent differences in transcriptional responses. In male mice, 50 genes were significantly regulated by binge drinking; in female mice, 70 genes were altered. Of these, 14 genes were regulated in both sexes, but most regulated genes were sex-specific. Notably, 10 of the 14 shared genes showed opposite regulation between sexes, while only four shared genes (Drd5, Grm4, Ranbp9, and Reln) were regulated in the same direction in both males and females.

Pathway analysis of the expression changes provided insight into the likely biological consequences of these sex-specific transcriptional responses. In female mice, the altered genes clustered around pathways related to hormone signaling and immune function, suggesting that repeated binge drinking influences endocrine and immune-related regulation in the female NAc. In male mice, the most prominent changes implicated neurotransmitter metabolism and nerve signaling pathways, indicating a primary impact on synaptic and neuronal signaling processes.

These divergent molecular responses matter for treatment development. Finn and colleagues emphasize that pharmacological strategies effective in one sex may not work in the other. The team reports that manipulating a pathway that was altered only in males reduced binge drinking in male mice but had no effect in females. This experimental result highlights the importance of accounting for sex when designing and testing pharmacotherapies for alcohol use disorder.

“A consideration of sex is critical in the development of potential pharmacological therapies for the treatment of alcohol use disorder,” Finn explains. “Our findings increase understanding of male and female differences in molecular pathways affected by repeated binge drinking and can help guide the design of sex-specific interventions.”

Future work will assess whether the observed gene expression changes translate into distinct behavioral or physiological consequences for males and females. Determining these links will be essential for translating molecular findings into effective, personalized treatment strategies for people with problematic binge drinking or alcohol dependence.

Funding: Supported by the U.S. Department of Veterans Affairs, VA Portland Health Care System, and the National Institute on Alcohol Abuse and Alcoholism (NIH).

Source and publication: Emma Duncan – Frontiers. The research article is titled “Binge Ethanol Drinking Produces Sexually Divergent and Distinct Changes in Nucleus Accumbens Signaling Cascades and Pathways in Adult C57BL/6J Mice” by Deborah A. Finn et al., published in Frontiers in Genetics (September 10, 2018).

The study characterized RNA expression differences in the nucleus accumbens of adult male and female C57BL/6J mice after seven binge ethanol drinking sessions compared with water-drinking controls. Focused qPCR array analysis quantified expression levels of 384 genes in a customized Mouse Mood Disorder array with emphasis on glutamatergic signaling. Significant regulation was identified for 50 genes in males and 70 genes in females, with 14 genes regulated in both sexes. Many shared genes showed opposite regulation between sexes, and the top regulated genes differed markedly by sex. Pathway analysis indicated hormone signaling and immune function changes in females, while neurotransmitter metabolism and nerve signaling were central targets in males. These results demonstrate a strong influence of sex on the transcriptional response to repeated binge drinking and underscore the importance of considering sex in developing pharmacotherapeutic targets for alcohol use disorder.

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