Cocaine-reinforced responding in rhesus monkeys: Pharmacological attenuation of the hypothalamic-pituitary-adrenal axis response

Intravenously self-administered cocaine produces a dose-dependent release of adrenocorticotropic hormone (ACTH) and cortisol in male rhesus monkeys. This study investigated whether the acute disruption of cortisol and/or ACTH release had any effect on ongoing cocaine-maintained responding. Four hypothalamic-pituitary-adrenal (HPA) axis inhibitors were examined: etomidate and ketoconazole, both of which are cortisol synthesis inhibitors; astressin, a peptidic corticotropin-releasing factor (CRF) antagonist that binds CRF₁ receptors predominantly in the pituitary gland; and dexamethasone, a highly selective glucocorticoid receptor agonist whose long- lasting effects reduce or abolish the endogenous release of ACTH and cortisol. The reinforcing effects of a range of cocaine doses, with or without pretreatment with an HPA inhibitor, were evaluated using a fixed ratio 30 time-out 10-min schedule of reinforcement in six male monkeys. Blood was sampled before, during, and after self-administration sessions. Self- administration of cocaine increased plasma cortisol and ACTH. Pretreatment with etomidate and ketoconazole dose-dependently inhibited the cocaine- induced rise in cortisol and, at the highest doses, produced a compensatory increase in ACTH release. Astressin and dexamethasone attenuated or abolished cocaine-induced cortisol and ACTH release. Despite the efficacy exhibited by these pretreatments and the variety of mechanisms by which they inhibited the HPA axis, there was no evidence for any change in cocaine-reinforced behavior (response rate or infusion number), an indication that acute changes in the ACTH or cortisol response to cocaine do not play a direct role in modulating cocaine-seeking behavior under these behavioral circumstances.