The role of progesterone and related neurosteroids in alcohol use and addiction

Background: Alcohol use disorder (AUD) remains a major global health challenge, showing faster progression and poorer treatment outcomes in females. Sex differences in AUD are increasingly recognized, with ovarian hormones playing a key role in modulating neural circuits involved in emotion regulation, reward processing, and stress responses. Both preclinical and clinical studies support sex-specific differences, highlighting the critical influence of hormonal status on risk, progression, and treatment outcomes in women. Progesterone and its neuroactive metabolites, such as allopregnanolone, have been implicated in stress regulation and alcohol-related behaviors, potentially via GABAergic mechanisms; however, the underlying mechanisms remain incompletely understood. Clinical studies further suggest that fluctuations in ovarian hormones across the menstrual cycle and hormonal transitions influence craving, stress sensitivity, relapse risk, and drinking patterns in women. This project investigates the impact of estradiol and progesterone on emotional and alcohol-related phenotypes, focusing on hormone-specific effects and their role in sex-specific vulnerability to AUD.

Method: Adult female C57BL/6J mice underwent ovariectomy (OVX) to control hormonal status. OVX-operated mice received subcutaneously implanted osmotic minipumps delivering vehicle (DMSO 10%), estradiol (0.025 mg/day), progesterone (0.425 mg/day), or both hormones. Emotional behaviors were assessed using open field (OF), elevated plus maze (EPM), light–dark box (LDB), novelty-suppressed feeding (NSF), and sucrose preference test (SPT). Voluntary ethanol consumption (4–16%) was measured in IntelliCages using a drinking-in-the-dark paradigm before and after OVX and hormone replacement. Alcohol reward sensitivity was assessed using a conditioned place preference (CPP) paradigm, which is currently ongoing.

Results: Ovariectomy (OVX) increased anxiety-related behaviors in adult female C57BL/6J mice. Specifically, OVX led to elevated anxiety in multiple behavioral tests, including Open Field (OF), Elevated Plus Maze (EPM), Light–Dark Box (LDB), and Novelty-Suppressed Feeding (NSF). OVX had no significant effect on depression-related behaviors or hedonia.

Hormone replacement modulated anxiety-related behaviors differently. Estradiol generally reduced anxiety- and depression-like behaviors across the tests. Progesterone showed context-dependent effects, producing anxiolytic effects in the EPM but increasing anxiety- and depression-like behaviors in other assessments. The combination of estradiol and progesterone fully reversed the anxiogenic effects of OVX, whereas individual hormone treatments alone did not completely counteract these effects.

OVX also increased alcohol-related behaviors, including voluntary alcohol consumption and alcohol-seeking behaviors measured in a drinking-in-the-dark paradigm. Estradiol or progesterone replacement alone reduced these behaviors and reversed OVX-induced escalation in alcohol drinking. In contrast, the combination of both hormones did not significantly reduce alcohol consumption. Estradiol effects on alcohol drinking were variable, while progesterone reduced the OVX-induced increase in alcohol consumption.

Conclusion: These findings demonstrate hormone-dependent modulation of emotional and alcohol-related behaviors in female mice. Estradiol and progesterone exert distinct, context-dependent, and partially dissociable effects. Progesterone may provide protective effects against ovariectomy-induced alcohol escalation, while estradiol consistently improves emotional phenotypes. These results enhance our understanding of sex-specific vulnerability to alcohol use disorder (AUD) and may inform hormone-based strategies for prevention and treatment in women.

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