Serotonin (5-HT) and 5-HT agonists act on multiple 5-HT receptor subtypes to increase corticosterone secretion. The present experiments describe the effects of a highly selective 5-HT2 receptor agonist DOI [(+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] on plasma corticosterone in conscious, unrestrained, male rats with indwelling arterial and venous catheters. DOI (500 micrograms/kg, i.v.) increased plasma corticosterone levels 6- to 7-fold from 15 to 60 min. Pretreatment with the central 5-HT2 antagonist LY 53857 (100 micrograms/kg, i.v.) blocked the effect of DOI on corticosterone secretion at all times. The peripheral 5-HT2 antagonist xylamidine (100 micrograms/kg, i.v.) attenuated the corticosterone response elicited 15 min after DOI but did not alter the 60-min response. In contrast, dexamethasone pretreatment (350 micrograms/kg, s.c.) attenuated the corticosterone response to DOI at 15 min, but abolished the response at 60 min. The increase in corticosterone levels elicited 5 min after the nonselective 5-HT agonist quipazine (3 mg/kg, i.v.) was also reduced by xylamidine. These data suggest that 5-HT2 receptor agonists increase corticosterone secretion initially, in part, through a direct adrenal mechanism not entirely dependent on adrenocorticotropin, and at later times via a central, dexamethasone-suppressible mechanism. This raises the possibility that endogenous 5-HT in the adrenal medulla may act as a local paracrine to participate in the regulation of corticosterone secretion from the adrenal cortex.