The relationship between stress and ethanol self administration: Circulating stress hormones and glutamate signaling in the hypothalamic paraventricular nucleus Public Deposited

This dissertation is a study of the peripheral and central components of the HPA axis using a macaque model of ethanol self-administration. Chapter 3 focuses on the primary stress hormones, adrenocorticotropic hormone (ACTH) and cortisol, under two distinct conditions, to test two hypotheses. The first is that long-term ethanol selfadministration selectively dampens stress hormones under low, but not mild, stress conditions. The second is that repeated forced abstinence elevates the HPA axis response under low stress conditions and leads to a dampened response to mild stress. Compared to pre-ethanol, there was a decrease in ACTH, independent of ethanol. The concentration of ACTH during open-access was negatively correlated with average daily intake, while low stress cortisol and the response to mild stress (both ACTH and cortisol) is generally preserved. Repeated abstinence revealed elevated cortisol under low stress and dampened ACTH under the mild stress condition. Chapter four focuses on parvocellular neurons in the hypothalamic paraventricular nucleus (PVN), the apex of the HPA axis. In females, a unique relationship between the relative glutamate immunogold density in putative recurrent terminals and average daily ethanol intake was found. When compared to ethanol-naïve controls, no differences were found in frequency of glutamatergic events in males with approximately 7.5-mo of open-access conditions while male macaques with a history of open-access and repeated abstinence had a higher frequency than ethanol-naïve controls. A binge concentration of ethanol (20mM) decreased the frequency of excitatory events in males with a history of ethanol access. Interestingly, ethanol-naïve males with no history of repeated abstinence did not respond to this concentration of ethanol while the ethanol-naïve subjects with repeated abstinence did, suggesting that the stress of repeated forced abstinence (indicated by elevated cortisol even in the ethanol-naïve controls) may sensitize the parvocellular PVN neurons to an intoxicating concentration of ethanol, perhaps contributing to the comorbidity of stress and ethanol consumption. These data suggest that glutamate signaling in the PVN is related to ethanol selfadministration, and altered by repeated periods of abstinence, although these relationships and alterations may differ between males and females.

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