Cocaine stimulates ACTH secretion by a corticotropin-releasing factor (CRF)-dependent mechanism in male rats, rhesus monkeys, and humans. To determine the generality of this effect, we examined the effects of acute cocaine administration on the pulsatile release of ACTH and cortisol in three ovariectomized (OVX) rhesus monkeys and compared its effects to stimulation with CRF. Venous blood samples were collected at 2-min intervals for 60 min before and after iv administration of cocaine (0.4 and 0.8 mg/kg) and CRF (1.0 and 10 micrograms/kg). Cluster analysis procedures were used to evaluate the pulsatile characteristics of ACTH and cortisol release. After placebo administration, an ACTH pulse frequency of 3 peaks/h was detected. After cocaine administration, plasma cocaine levels peaked at 92 +/- 3.0 and 201 +/- 60 ng/mL within 2 min. However, in contrast to normal intact males, cocaine did not stimulate the pulsatile release of ACTH in OVX females. Cocaine (0.4 mg/kg) decreased ACTH incremental peak height and valley levels compared with pre-cocaine values, and a higher dose of cocaine produced no changes in ACTH release. Bolus injection of a low dose of CRF (1.0 micrograms/kg, iv) significantly increased ACTH incremental peak height (P < 0.05), and a higher dose of CRF (10 micrograms/kg) increased ACTH peak amplitude, percentage increase in peak amplitude, area under the peaks, and incremental peak heights as well as ACTH valley level and nadir (10 micrograms/kg, iv) (P < 0.05). ACTH pulse frequency did not change after CRF or cocaine administration. Pulsatile release of cortisol was 2.7 peaks/h under placebo conditions and did not change after cocaine or CRF administration. Cortisol pulse amplitude was increased after low and high doses of CRF. High doses of CRF (10 micrograms/kg) also increased the mean level of cortisol valleys. In summary, we found that CRF but not cocaine stimulated pulsatile ACTH and cortisol release in OVX rhesus monkeys. The profound ACTH response to CRF challenge suggests that the CRF sensitivity and the ACTH release capacity of the anterior pituitary corticotroph cells were intact. The lack of stimulatory effects of cocaine on the hypothalamic-pituitary-adrenal axis in OVX monkeys, in contrast to normal male monkeys, may reflect the absence of gonadal steroids.