The mechanisms by which the serotonin2A/2C (5-HT2A/2C) receptor agonist, (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) increase adrenocortical secretion were examined. Intraperitoneal (i.p., 2 mumol/kg) and intracerebroventricular (i.c.v., 0.1 pmol -40 nmol) administration of DOI increased plasma corticosterone (CS) concentrations. Administration of the 5-HT2A/2C antagonist, ketanserin (i.c.v.) also increased adrenocortical secretion, although the more selective 5-HT2A/2C antagonist, 6-methyl-1-(1-methylethyl)-ergoline-8 beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857) did not. In pentobarbital-anesthetized rats, DOI (i.c.v.) decreased adrenocortical secretion, whereas i.p. administration increased adrenocortical secretion. Ketanserin and LY 53857 (i.c.v.) failed to block CS responses after i.p. DOI, indicating that these increases were not principally due to central 5-HT2 receptor activation; only i.p. administration of ketanserin was able to block responses to DOI. Adrenocortical responses to DOI (i.p.) were preserved after lesions of the hypothalamic paraventricular nucleus or posterior hypothalamic deafferentations. However, responses to DOI were almost abolished in hypophysectomized animals, whereas neurohypophysectomy and treatment with dexamethasone were without effect. Adrenocortical responses after DOI (i.p.) were attenuated in medullectomized and in combined 6-hydroxydopamine-sympathectomized/medullectomized animals, but responses to i.c.v. DOI were not affected by such treatment. 6-Hydroxydopamine lesions of the ventral noradrenergic ascending bundle abolished the response to i.p. DOI, indicating that activation of central noradrenergic systems mediates the increases in adrenocortical secretion. These results demonstrate that central and peripheral 5-HT2 receptors differentially regulate adrenocortical secretion, the central component being sensitive to pentobarbital anesthesia and the peripheral component being dependent upon central and peripheral noradrenergic systems.