Neuroendocrine Implications for Coping and Alcohol Consumption in Response to Exercise Restriction

The purpose of our study is to investigate the role that gonadal hormones and β-endorphin play in alcohol consumption in response to exercise restriction in a mouse model. Men and women consume alcohol in different manners from each other, both in terms of general consumption and in the factors motivating consumption. The murine model of alcohol self-administration that we utilize in this study represents both facets of this sex difference; female mice consume more alcohol than male mice and also are more likely to significantly increase their consumption when restricted from voluntarily accessing running wheels. We hypothesized in our first experiment that if activational effects of ovarian hormones promote elevated vulnerability to exercise-restricted alcohol consumption, then ovariectomy would reduce the propensity to drink more alcohol when running wheels were unavailable. Our next hypothesis was that if activational effects of testicular hormones protect against exercise restriction-induced alcohol consumption, then castration would enhance alcohol consumption in response to wheel restriction compared to controls. To test these hypotheses, 47 female and 33 male mice underwent gonadectomy surgery, sham surgery, or were surgery-naïve. Using a limited access paradigm where animals had access to 20% ethanol solution for two hours each day, we measured alcohol consumption when mice had voluntary access to a running wheel, compared consumption when exercise-restriction stress was imposed by restricting access to the running wheels. We found no effects of either ovarian hormones or testicular hormones on alcohol consumption in response to exercise restriction, although ovariectomy did decrease overall alcohol consumption, consistent with ovarian hormones mediating the tendency for females to self-administer higher levels of alcohol overall. Our second set of studies examined the effects of β-endorphin on exercise restriction-induced alcohol consumption. β-endorphin negatively regulates the stress response, is released in response to alcohol consumption, and depleted levels of the hormone have been clinically correlated with elevated risk for excessive alcohol consumption. We hypothesized that effective self-medication with alcohol is dependent on β-endorphin inhibition of the stress axis. This may be implicated in the observed escalation in alcohol self-administration in response to exercise restriction in females and may interact with testicular hormones in male mice. To test these hypotheses, transgenic mice with varying levels of β-endorphin were subjected to the exercise-restriction self-administration paradigm. The male mice in these experiments were also subjected to either castration or sham surgeries to facilitate an understanding of the interaction between testicular hormones and β-endorphin levels. In females, low β-endorphin conferred enhanced sensitivity to drinking in response to wheel restriction, but this effect was not present in male subjects, regardless of gonadal condition. Female mice also displayed genotypic differences in plasma corticosterone levels and corticotropin-releasing hormone mRNA content in stress-related brain regions, suggesting alterations in stress-response activity as a function of β-endorphin levels. Together these results suggest that activational effects of gonadal hormones do not explain observed sex differences in exercise restriction-induced alcohol self-administration; and β-endorphin deficiency confers elevated risk for exercise restriction-induced alcohol consumption in a manner that does not interact with testicular hormones. With further investigation, the data presented in this thesis could assist in the development of individualized treatment and prevention plans in alcohol use disorder