These studies were undertaken to test the hypothesis that stimulation of the central noradrenergic and adrenergic pathways activates the hypothalamic-pituitary-adrenal axis in vivo in the conscious sheep. Blood samples were taken at 10-min intervals over 4 h to establish the baseline state, and then each animal received an intracerebroventricular (icv) injection of NaCl (control animals) or catecholamine [norepinephrine (NE) or epinephrine (EPI)]. A more frequent rate of venous sampling was used for the 30-min period after the icv injection, after which time the 10-min rate of blood sampling was continued for another 3.5 h.NaCl (n = 4) caused no change in pituitary-adrenal secretion. In contrast, 10 μg NE (n = 4) caused acute 1.9- and 3.2-fold increases in mean plasma ACTH and Cortisol levels over the 1 h period post injection, and 1.6- and 2.3-fold increments in their concentrations over the 4 h postinjection period. Although 10 μg EPI (n = 4) did not elevate mean plasma ACTH, it produced significant 1.7- and 1.5-fold increases in plasma Cortisol during the 1- and 4-h periods post injection. However, when 100 μg EPI was injected (n = 4), acute 9.5- and 5.5-fold increases in plasma ACTH and Cortisol were seen over the 1 h period post injection, and 6.1- and 4.2-fold increments in their plasma concentration were noted during the entire post-injection period. To determine the predominant site of action of the catecholamines, we also examined the ability of NE and EPI to release ACTH from cultured ovine anterior pituitary cells. NE and EPI (10-9-10-6M) stimulated the release of ACTH in a dose-dependent manner, but with maximal increments only 1.5-fold greater than the basal secretion. NE and EPI also increased the maximal ACTH response to CRF, but did not alter the maximal ACTH release induced by arginine vasopressin.From these findings, we derive the following conclusions: 1) activation of the central noradrenergic and adrenergic pathways stimulates the pituitary-adrenal axis, and the noradrenergic input appears more important in vivo in the sheep; 2) since NE and EPI cause only a modest release of ACTH from the anterior pituitary, the central catecholaminergic pathways stimulating the pituitary-adrenal axis act predominantly at one or more suprahypophysial brain sites; 3) the acute and sustained increments in ACTH and Cortisol secretion in response to central catecholaminergic stimulation are therefore likely to be due to the release of one or more hypothalamic ACTH-releasing factors; and 4) the ability of NE and EPI injected icv to cause sustained pituitary-adrenal secretion indicates that the central noradrenergic and adrenergic pathways, when sufficiently activated, are also capable of disrupting the negative feedback effects of the glucocorticoids on those areas of the brain concerned with the regulation of the hypothalamic-pituitary-adrenal axis.