When I heard about Dr. Jessica Hoffman’s research on alcohol self-administration, one finding really caught my attention. Female mice were drinking more alcohol than males, which surprised me because I feel like we usually hear more about alcoholism in men. It made me wonder what was causing this difference. Was there something about female mice’s biology that made them more likely to drink alcohol? This question led me to look more closely at the research ad explore whether hormones could play a role.
Jessica Hoffman and her colleagues were originally studying whether targeting certain receptors in the brain could help reduce alcohol consumption. Specifically, they focused on AMPA receptors, which are involved in communication between neurons and processes like learning and reward. They also studied TARP γ-8 a protein that helps regulate some of these receptors. Instead of blocking AMPA receptors throughout the brain, they tested a compund called JNJ-55511118, which targets AMPA recepros associated with TARP γ-8. The idea was to see whether this more specific approach could reduce alcohol self-administration without some of the side effects that come with blocking AMPA receptors more broadly.
In their experiment mice were trained to press a lever to receive a sweetend slcohol solution. Before any treatment was given, the female mice pressed the lever more often and consumed more alcohol than the males. The researchers also found that JNJ-55511118 reduced alcohol administration in males, but there was no reduction in females. Although the differnece in treatment response stood out, I was still curious about what caused the females to drink more even before the treatment began.
A study by Jean Rivera-Irizarry and her colleagues offered a possible piece of the answer. They investigated how estrogen affects alcohol drinking in female mice and found that alcohol consumption increased when estrogen levels wwre higher during the estrous cycle. They also identified a mechanism in a brain region caleed the bed nucleus of the stria terminalis, which os involved in stress and reward-related behaviors. Estrogen acted through estrogen receptr alpha and increased the activity of corticotropin-releasing factor neurons, promoting alcohol drinking.when the reserachers interfered with this pathway, alcohol consumption decreased. However, reducing estrogen did not have the same effect on sucrose consumption, suggesting the findings were not simply explained by a general decrease in the desire fpr reward.
Of course, this does not prove that estrogen was responsible for the hiher alcohol consumption in Hoffman’s female mice or explain why the treatment worked differently between males and females. However, they did mention that they had not measured the estrous cycle during their experiment, meaning hormonal fluctuations were one possible factor thye could not fully account for. Rivera-Irizarry’s findings suggest that these hormonal changes may actually influence the brain circuits involved in alcoholdrinking, making them worth investigating rather than simply treating them as anotehr variable.
Males and females are not biologically identical, so it makes sense to consider those differences when studying alcohol use disorder. Hormone and reproductive cycles can influnce how certain brain systems fucntion, which means that a treatment that works in males might not necessarily work in females. Understanding these differences could be an important step toward developing treatments that account fro both sexes, instead of assuming that what works for one will automatically work fro the other.
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
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