Adaptations in Basal and Hypothalamic-Pituitary-Adrenal-Activated Deoxycorticosterone Responses Following Ethanol Self-administration in Cynomolgus Monkeys.

Vanessa A Jimenez,Patrizia Porcu,A Leslie Morrow,Kathleen A Grant

doi:10.3389/fendo.2017.00019

Abstract

Acute ethanol activates the hypothalamic–pituitary–adrenal (HPA) axis, while long-term exposure results in a blunted neuroendocrine state, particularly with regards to the primary endpoint, cortisol, the primary glucocorticoid produced in the adrenal cortex. However, it is unknown if this dampened neuroendocrine status also influences other adrenocortical steroids. Plasma concentration of the mineralocorticoid and neuroactive steroid precursor deoxycorticosterone (DOC) is altered by pharmacological challenges of the HPA axis in cynomolgus monkeys. The present study investigated HPA axis regulation of circulating DOC concentration over the course of ethanol (4% w/v) induction and self-administration in non-human primates (Macaca fasciculata, n = 10). Plasma DOC, measured by radioimmunoassay, was compared at baseline (ethanol naïve), during schedule-induced polydipsia, and following 6-months of 22 h/day access to ethanol and water. The schedule induction of ethanol drinking did not alter basal DOC levels but selectively dampened the DOC response to pharmacological challenges aimed at the anterior pituitary (ovine corticotrophin-releasing hormone) and adrenal gland (post-dexamethasone adrenocorticotropin hormone), while pharmacological inhibition of central opioid receptors with naloxone greatly enhanced the DOC response during induction. Following 6 months of ethanol self-administration, basal DOC levels were increased more than twofold, while responses to each of the challenges normalized somewhat but remained significantly different than baseline. These data show that HPA axis modulation of the neuroactive steroid precursor DOC is markedly altered by the schedule induction of ethanol drinking and long-term voluntary ethanol self-administration. The consequences of chronic ethanol consumption on HPA axis regulation of DOC point toward allostatic modification of hypothalamic and adrenal function.

Highlights

Endogenous stress systems are sensitive to pharmacological doses of ethanol as well as the conditions under which ethanol is made available to the organism
Compared to baseline (0.28 ± 0.06 ng/ml) and induction (0.37 ± 0.16 ng/ml), DOC had increased twofold following 6-months of ethanol self-administration (0.74 ± 0.19 ng/ml; p < 0.0001). This was intriguing, as we have previously reported a positive correlation between plasma adrenocorticotropin hormone (ACTH) and DOC [26] and that ACTH is elevated during ethanol induction [32]
The state of the HPA axis within a phase of ethanol self-administration appears reliable as evidenced by elevated ACTH concentrations during ethanol induction, a finding we have previously reported in different samples from the same animals [32]

Summary

Introduction

Endogenous stress systems are sensitive to pharmacological doses of ethanol as well as the conditions under which ethanol is made available to the organism. Other studies have found abstinent alcoholics have greater basal ACTH [9], lower levels of the cortisol precursor 11-deoxycortisol and a reduced cortisol response to exogenous ACTH administered after dexamethasone [10]. ACTH [early abstinence [11, 12]] and cortisol after pituitary stimulation by CRH are lower in abstinent alcoholics [1-month abstinence [9]]. Abstinent alcoholic men [10], but not women [14], had lower dexamethasone (8 mg, i.v.) suppression of ACTH and cortisol compared to controls. Overall these data suggest adaptations during chronic ethanol intoxication in state dependent and likely occur at each level of the HPA axis

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