Investigating the Influence of Sex Hormones on Endocannabinoid Release in Response to Voluntary Wheel Running

Regular exercise promotes mental and physical wellbeing, while sedentary lifestyles are associated with an increased risk of developing various chronic health conditions. The endocannabinoid (eCB) system plays a dual role in exercise, functioning both as a product of physical activity and a regulator of future exercise behavior. This unique characteristic suggests that eCBs may contribute to a positive feedback loop, where their physiological effects during exercise enhance the likelihood of future physical activity. The effect of exercise on eCB levels has been well studied, but additional research is needed to elucidate potential roles of sex hormones in the eCB system in response to exercise. In the present study, we found that male rats that participated in an acute voluntary wheel running (VWR) paradigm had significantly higher levels of serum eCBs than their sedentary counterparts (Anandamide (AEA): p =0.0396, oleic acid: p =0.0268, palmitoylethanolamide (PEA): p =0.0003). We have shown previously that estrogen plays a role in regulating VWR activity in female rats (Mathis et al., 2024), so to explore the effects of acute exercise on the eCB systems of female rats, we artificially synchronized their estrous cycles through ovariectomy (OVX) followed by estrogen supplementation with estradiol benzoate (EB). Using this model, we planned to investigate whether estrogen alone could induce eCB release. We found significantly higher levels of several serum eCBs in the EB-treated running group compared to those receiving vehicle treatment (Docosahexaenoic acid (DHA): p =0.0094, eicosapentaenoic acid (EPA): p =0.0189, oleic acid: p =0.0421, linoleic acid: p =0.0293). Interestingly, this difference was not observed in the sedentary group receiving the same treatment. However, this model does not replicate the other hormonal fluctuations occurring during the estrous cycle that could impact VWR or the eCB system. To mitigate this difference, we recently conducted this experiment with intact female rats with synchronized estrous cycles, and serum eCB measurements are currently underway. This development will allow us to further explore the interplay between sex hormones and the eCB system, potentially yielding crucial insights into the mechanisms governing physical activity. Ultimately, uncovering these mechanisms can help to refine strategies to promote regular exercise in humans. Funded by the American Heart Association and Iowa Osteopathic Education and Research Foundation This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.