Cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis in rodents and in humans. This study examined the acute effects of cocaine (0.4 and 0.8 mg/kg) and saline placebo on pulsatile adrenocorticotropic hormone (ACTH) and cortisol release in seven male rhesus monkeys. Pulsatile ACTH and cortisol release were evaluated with an intensive (2-min) venous blood sampling procedure and cluster analysis. In addition, the behavioral responses to cocaine were analyzed to assess the relationship between HPA axis activation and behavior. Although analysis of group data revealed significant (P < .05) increases in pulse amplitude and incremental peak height of ACTH and cortisol release after cocaine (0.8 mg/kg) administration, examination of individual data indicated that this effect was not consistent across all monkeys. Cocaine (0.8 mg/kg) increased ACTH plasma levels within 4.7 +/- 1.3 min (P < .05) and amplitude-related characteristics (P < .05) of pulsatile ACTH and cortisol release only in those animals that subsequently showed behavioral stimulation (high responders: n = 3). The frequency of pulsatile ACTH and cortisol remained unchanged by cocaine. Cocaine (0.8 mg/kg) decreased the mean amplitude of ACTH peaks with no changes in pulsatile cortisol release in the four monkeys that showed no behavioral stimulation (low responders). These differences in pulsatile ACTH and cortisol release patterns after cocaine could not explained by different plasma cocaine levels. Peak plasma cocaine levels averaged 63.1 +/- 13.4 and 78.0 +/- 21.4 ng/ml within 2 min after lower dose and 183.3 +/- 52.3 and 204.3 +/- 50.8 ng/ml after higher dose of cocaine in high- and low responder groups, respectively (P > .05; N.S.). Base-line cortisol, but not ACTH, levels were higher (P < .05) in low responders before administration of 0.8 mg/kg of cocaine. Peak and valley characteristics of base-line cortisol release were higher in low responders than in high responders and an inverse relationship was found between basal cortisol levels and postcocaine ACTH release and behavior. In summary, cocaine stimulated the pulsatile ACTH and cortisol release by increasing the amplitude of secretory episodes in behaviorally responsive monkeys.