The regulation of the hypothalamic-pituitary-adrenal axis by dopamine is not fully understood. Therefore, we have studied the effect of dopamine, metoclopramide, a D-2 receptor antagonist, and fenoldopam, a specific D-1 receptor agonist, on ACTH and cortisol levels in normal subjects. Normal women received 5-h infusions of either glucose (N = 6) or dopamine at rates of 0.04 (N = 6), 0.4 (N = 6) and 4.0 micrograms.kg-1.min-1 (N = 8). After 3 h, 10 mg metoclopramide was given iv. No intergroup differences regarding ACTH and cortisol levels were observed (p greater than 0.05). In a second study six women received dopamine (4.0 micrograms.kg-1.min-1) or glucose for 18 h. During the infusions cortisol and ACTH levels were similar on the two study days. Administration of metoclopramide (10 mg) after 17 h induced a significant increase in cortisol levels during dopamine infusion (p less than 0.05), whereas no effect was observed during placebo infusion. ACTH levels were unaffected by metoclopramide. In a third study, 9 normal women and 9 normal men received fenoldopam (0.5 micrograms.kg-1.min-) or placebo infusions for 3 h. In males, median ACTH and cortisol levels were significantly lower (p less than 0.05) during fenoldopam compared with placebo infusion. In contrast, fenoldopam did not affect ACTH and cortisol levels in normal women. The results suggest that the effect of dopamine D-1 receptor stimulation on ACTH and cortisol secretion is mainly at the hypothalamic level and that this effect is sex-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)