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

Intravenously self-administered cocaine produces a dose-dependent release o f adrenocorticotropic hormone (ACTH) and cortisol in male rhesus monkeys. T his study investigated whether the acute disruption of cortisol and/or ACTH release had any effect on ongoing cocaine-maintained responding. Four hypo thalamic-pituitary-adrenal (HPA) axis inhibitors were examined: etomidate a nd ketoconazole, both of which are cortisol synthesis inhibitors; astressin , a peptidic corticotropin-releasing factor (CRF) antagonist that binds CRF , receptors predominantly in the pituitary gland; and dexamethasone, a high ly selective glucocorticoid receptor agonist whose longlasting effects redu ce or abolish the endogenous release of ACTH and cortisol. The reinforcing effects of a range of cocaine doses, with or without pretreatment with an H PA inhibitor, were evaluated using a fixed ratio 30 time-out 10-min schedul e of reinforcement in six male monkeys. Blood was sampled before, during, a nd after self-administration sessions. Self-administration of cocaine incre ased plasma cortisol and ACTH. Pretreatment with etomidate and ketoconazole dose-dependently inhibited the cocaine-induced rise in cortisol and, at th e highest doses, produced a compensatory increase in ACTH release. Astressi n and dexamethasone attenuated or abolished cocaine-induced cortisol and AC TH release. Despite the efficacy exhibited by these pretreatments and the v ariety of mechanisms,by which they inhibited the HPA axis, there was no evi dence for any change in cocaine-reinforced behavior (response rate or infus ion number), an indication that acute changes in the ACTH or cortisol respo nse to cocaine do not play a direct role in modulating cocaine-seeking beha vior under these behavioral circumstances.