Adrenal steroid hormones and ethanol self-administration in male rhesus macaques

Abstract

Rationale Hypothalamic-pituitary-adrenal (HPA) axis hormones have neuroactive metabolites with receptor activity similar to ethanol. Objectives The present study related HPA hormones in naïve monkeys to ethanol self-administration. Methods Morning plasma adrenocorticotropic hormone (ACTH), cortisol, deoxycorticosterone (DOC), aldosterone and dehydroepiandrosterone-sulfate (DHEA-S) were measured longitudinally in male rhesus macaques (Macaca mulatta) induced to drink ethanol followed by access to ethanol (4% w/v, in water) and water 22 hours/day for 12 months. Results During ethanol access, DOC increased among non-heavy (average intake over 12 months ≤ 3.0 g/kg/day, n = 23) but not heavy drinkers (> 3.0 g/kg/day, n = 9), aldosterone was greater among heavy drinkers after 6 months. The ratio of DOC/aldosterone decreased only among heavy drinkers after 6 or12 months of ethanol self-administration. ACTH only correlated significantly with DHEA-S, the ratio of cortisol/DHEA-S and DOC after the onset of ethanol access, the former two just in heavy drinkers. Baseline hormones did not predict subsequent ethanol intake over 12 months, but baseline DOC correlated with average blood-ethanol concentrations (BEC), among all monkeys and heavy drinkers as a group. During ethanol access, aldosterone and DOC correlated and tended to correlate, respectively, with 12-month average ethanol intake. Conclusions Ethanol self-administration lowered ACTH and selectively altered its adrenocortical regulation. Mineralocorticoids may compensate for adrenocortical adaptation among heavy drinkers and balance fluid homeostasis. As DOC was uniquely predictive of future BEC) and not water intake, to the exclusion of aldosterone, GABAergic neuroactive metabolites of DOC may be risk factors for binge drinking to intoxication.

Twelve months of voluntary heavy alcohol consumption in male rhesus macaques suppresses intracortical bone remodeling

“…Furthermore, alcohol may act as an endocrine disruptor by altering levels of and/or skeletal response to vitamin D, sex hormones (e.g., estrogen and testosterone), parathyroid hormone, pituitary-derived hormones (e.g., growth hormone), and adipocyte-derived hormones (e.g., leptin) [24, 25]. Alcohol self-administration lowered dehydroepiandrosterone-sulfate and selectively altered its adrenocortical regulation in rhesus macaques but did not lower testosterone levels [73]. Low 25-hydroxyvitamin D levels, due to poor nutritional status, are often found in chronic alcohol consumers [46, 47].…”

Studies using macaque monkeys to address excessive alcohol drinking and stress interactions

“…We have also observed the same relationship between age and heavy alcohol intake in female rhesus macaques (unpublished observation). Of the HPA-related hormones studied in the late adolescent/young adult male monkeys (ACTH, cortisol, deoxycorticosterone (DOC), DHEA-S, and aldosterone) the neurosteroid DOC at baseline was uniquely predictive of attaining high BECs during open-access self-administration (Helms et al, 2014b). Thus, both the young adult stage and circulating DOC appear related to risk for heavy drinking, although these factors cannot be disentangled with the current datasets.…”

“…In this context, there is not a general lack of ACTH sensitivity at the adrenal gland, as hormones from each layer of the adrenal cortex were not uniformly desensitized. Specifically, male rhesus macaques have significantly lower basal ACTH following long-term daily alcohol self-administration while the adrenal steroids are differentially affected (Helms et al, 2014b). Cortisol (secreted from the zona fasciculata) remained constant across the experimental phases, similar to sulfated dehydroepiandrosterone (DHEA-S, an androgen secreted from the zona reticularis).…”

“…Mineralocorticoids, however, were significantly increased during open-access conditions. Specifically, aldosterone and deoxycorticosterone (DOC; mineralocorticoids secreted from the zona glomerulosa) increased significantly during open-access compared to pre-alcohol (Aoun et al, 2017; Helms et al, 2014b). Additionally, DOC measured at baseline and after 12-months of open-access was negatively correlated with average BEC during open access conditions, while aldosterone was related to the volume of water and alcohol consumed (Helms et al, 2014b).…”

Higher pretreatment blood pressure is associated with greater alcohol drinking reduction in alcohol-dependent individuals treated with doxazosin

“…Finally, in order to explore whether the putative moderator effect of BP may also relate to peripheral neuroendocrine biomarkers, we also assessed blood levels of cortisol and aldosterone. In fact, both hormones may play a role in BP tone (Lyngso et al, 2016; Ullian, 1999), as well as in excessive alcohol drinking (Helms et al, 2014; Leggio et al, 2008; Spencer and Hutchison, 1999). …”