Same Alcohol, Different Brain: The Role of Sex Differences in Alcohol Consumption

Alcohol use disorder affects millions of people, but understanding why some individuals are more vulnerable to alcohol use than others is complicated. Alcohol does not affect everyone in exactly the same way, which raises an important question: can we assume that the same neural mechanism will influence alcohol-related behavior in the same way in males and females? This became especially interesting to me while learning about Dr. Jessica Hoffman's research on alcohol self-administration. 

Researchers Jessica Hoffman and her colleagues explored whether selectively targeting a specific type of AMPA receptor could reduce alcohol self-administration. AMPA receptors are glutamate receptors involved in processes such as learning and reward. More specifically, they investigated TARP γ-8, a protein that regulates certain AMPA receptors in specific brain regions. Instead of broadly blocking AMPA receptors throughout the brain, the researchers tested JNJ-55511118, a compound that selectively inhibits AMPA receptors associated with TARP γ-8. Their goal was to determine whether targeting this more specific system could reduce alcohol self-administration while potentially avoiding some of the side effects associated with broadly inhibiting AMPA receptors.

While the study was mainly investigating this potential target, one result caught my attention for a different reason. Before receiving any treatment, female mice showed significantly greater alcohol self-administration than males. They  made more active lever responses, earned more alcohol reinforcers, and ultimately consumed more alcohol. After treatment with JNJ-55511118, alcohol self-administration decreased in males, while the same reduction was not observed in females. Although the difference in response to treatment stood out, I kept coming back to an even earlier question: why were the female mice drinking more alcohol in the first place?

A more recent study offers a possible piece of the answer. Lia Zallar and her colleagues investigated how ovarian estrogen influences alcohol drinking behavior in female mice. They found that female mice displayed greater binge alcohol drinking when estrogen was high during the estrous cycle than when it was low. More importantly the researchers identified a neural mechanism that could help explain this behavior. Estrogen acted through membrane-associated estrogen receptor alpha (ERα) in the bed nucleus of the stria terminalis (BNST), a brain region involved in stress and reward-related behaviors. This signaling increased the excitation of corticotropin-releasing factor (CRF) neurons and promoted alcohol drinking. When they interfered with this estrogen signaling pathway, alcohol consumption decreased. This effect also appeared to be specific to alcohol rather than simply increasing general reward-seeking behavior, since acutely reducing estrogen did not similarly decrease sucrose consumption.

This research does not mean that estrogen explains why the female mice in Hoffman's study consumed more alcohol, or why JNJ-55511118 reduced alcohol self-administration in males but not in females. However, it provides a possible explanation for the difference  in baseline alcohol consumption. In fact, Hoffman and her colleagues acknowledged that the estrous cycle was not measured in their experiment and discussed hormonal fluctuations as one factor that could potentially influence alcohol self-administration. That makes Zallar's findings even harder to ignore because they suggest that hormonal state may actively change neural circuits involved in alcohol drinking rather than simply being another variable researchers need to control.  

The difference between the male and female mice may seem like a small detail compared with the main purpose of Hoffman's study, but Zallar's research shows why findings like this should not be overlooked. If hormonal state can change the neural mechanisms that influence alcohol drinking, then differences between males and females may be more than just experimental variability. They could reveal important parts of the biology behind alcohol  use that would otherwise go unnoticed. As researchers continue looking for new ways to understand and treat alcohol use disorder, paying attention to these differences may be just as important as finding the similarities. 

References: 

Hoffman, J. L., et al. (2021). Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ-8 with JNJ-55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self-administration.Alcoholism: Clinical and Experimental Research, 45(7), 1424–1435.

Zallar, L. J., Rivera-Irizarry, J. K., Hamor, P. U., et al. (2024). Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice. Nature Communications, 15, 10725. https://doi.org/10.1038/s41467-024-54737-6