Several studies have argued that the hypothalamo-pituitary-adrenal (HPA) axis is of significance to behavioral effects evoked by drugs of abuse (e.g. cocaine). The role of the HPA axis in the subjective effects of cocaine was investigated in rats trained to discriminate cocaine (10 mg/kg, ip, -15 min) from saline (ip, -15 min) in a two-choice, water-reinforced fixed ratio (FR) 20 drug discrimination paradigm. In substitution tests, neither the exposure to a novel environment nor the social defeat stress, applied to rats after a dose of cocaine (2.5 mg/kg) which induced a ca. 42% drug-appropriate responding, influenced cocaine discrimination. Given alone, corticosterone (20 and 40 mg/kg, sc, -60 min) elicited a ca. 7% drug-appropriate responding. Combined injections of corticosterone and cocaine (0.625-5 mg/kg) did not affect the dose-response curve for cocaine. Surgical adrenalectomy did not modify the effects of cocaine; using a cumulative dosing procedure in the drug discrimination paradigm we found, that the dose-response curves for cocaine in adrenalectomized rats and sham-operated controls practically did not differ. Ketoconazole (an inhibitor of adrenocorticosteroid synthesis; 50 mg/kg, ip) given acutely (60 min) did not affect cocaine discrimination. Given subacutely (24, 16 and 1 h before tests), ketoconazole (50 mg/kg) produced a left-ward shift in the dose-response curve for cocaine and decreased its ED50 value. Another inhibitor of corticosterone secretion, metyrapone (50 mg/kg, sc), given acutely (120 min) did not affect the dose-response curve for cocaine. However, repeated injections (24, 16 and 2 h before tests) of metyrapone (50 mg/kg) with different doses of cocaine resulted in a rightward shift in the dose-response curve for cocaine and an increase in its ED50 value. The obtained results seem to exclude any role of the HPA axis in mediating subjective effects of cocaine, since neither corticosterone and stress nor adrenalectomy modified the discriminative stimulus effects of cocaine in rats. The reduction and potentiation of cocaine discrimination following subacute metyrapone and ketoconazole, respectively, may depend on changes in the levels of intermediate neurosteroids "upstream" from corticosterone in its biosynthesis pathway.