The acute administration of cocaine (5-20 mg/kg) to rats produced a dose-dependent elevation in both serum corticosterone and plasma adrenocorticotrophic hormone (ACTH). These elevations were maximal at 30 min and returned to basal values by 60 min. The dopamine (DA) uptake blockers GBR12909 and nomifensine, the norepinephrine uptake blocker desipramine, as well as the serotonin (5-HT) uptake blocker fluoxetine, also stimulated hypothalamo-pituitary-adrenal (HPA) axis activity, whereas the local anesthetic procaine did not. Pretreatment with haloperidol (0.2 mg/kg) significantly attenuated the elevations in corticosterone and ACTH elicited by cocaine, as well as the elevation in ACTH produced by GBR12909. Higher doses of haloperidol (1 or 3 mg/kg) also attenuated the HPA response to cocaine and GBR12909. Pretreatment with the D1 antagonist SCH23390, the D2 antagonist sulpiride, the D1/D2 antagonist fluphenazine, or the 5-HT2 antagonist ketanserin significantly decreased the ACTH elevations after cocaine. In contrast, neither the 5-HT antagonist cyproheptadine, the alpha-1 antagonist prazosin nor the beta adrenergic antagonist propranolol attenuated the ACTH response to cocaine. The present results suggest an important stimulatory role for DA in regulation of HPA activity, and a role for both DA and 5-HT in the adrenocortical stimulation by cocaine. Both D1 and D2 receptors appear to be involved in the dopaminergic component of this response.