Adaptations in basal and hypothalamic-pituitary-adrenal-mediated deoxycorticosterone responses following ethanol self-administration in Cynomolgus monkeys

Acute ethanol activates the hypothalamic-pituitary-adrenal (HPA) axis, while long-term exposure results in a dampened neuroendocrine state, particularly with regards to the primary endpoint, cortisol. However, it is unknown if this dampened neuroendocrine status also influences other adrenocortical steroids. Plasma levels of the mineralocorticoid and neuroactive steroid precursor deoxycorticosterone (DOC) are altered by pharmacological challenges of the HPA axis in cynomolgus monkeys. The present study is an extensive investigation of the mechanisms related to HPA axis activation that regulate DOC concentration over the course of ethanol (4% w/v) induction and self-administration in non-human primates. Acute ethanol (1.0 and 1.5 g/kg; delivered by intragastric gavage) suppresses circulating DOC in naïve animals. During ethanol induction, the lower dose was less effective in suppressing DOC, an effect that recovered during self-administration. Similarly, we found that during induction, the DOC response was significantly dampened in response to pharmacological stimulation of the anterior pituitary (ovine corticotropin releasing hormone) and adrenal cortex (post-dexamethasone ACTH), but sensitized at the level of the hypothalamus (naloxone) while no significant differences in basal levels were found. After 6-months of ethanol self-administration, the response to each pharmacological challenge, although still significantly different than baseline, had returned towards baseline while basal DOC was significantly increased. These data indicate that HPA axis modulation of DOC is markedly altered by schedule-induction and long-term voluntary ethanol self-administration. The consequences of chronic ethanol consumption on HPA axis function involve adaptation at all three levels of the stress axis and support the development of an allostatic state.