Female CF1 mice were given L-5-hydroxytryptophan (5-HTP), quipazine, or 6-methoxy-1,2,3,4-beta-carboline (6-MeO-THBC) in conjunction with various serotonergic drugs to determine if the pituitary-adrenal stimulation produced by the former compounds is serotonergically mediated. Corticosterone (CS) responses to 5-HTP were uninfluenced by pretreatment with a tryptophan hydroxylase inhibitor, p-chlorophenylalanine (PCPA), but were significantly potentiated by a serotonin (5-HT) reuptake inhibitor (Lilly 110140), attenuated by two 5-HT receptor blockers, cyproheptadine and methergoline, and almost completely abolished by 2 extracerebral aromatic L-amino acid decarboxylase inhibitors, MK 486 and a low dose of Ro 4-4602. It was also established that L-tryptophan could stimulate pituitary-adrenal activity in animals pretreated with the monoamine oxidase (MAO) inhibitor pargyline. Serotonergic drugs were generally not as effective in modulating the responses to quipazine and 6-MeO-THBC. It is concluded that (1) 5-HTP stimulates pituitary-adrenal activity in mice by being converted to 5-HT and acting on 1 or more groups of serotonergic receptors; (2) these receptors are located either in an area of the brain outside of the blood-brain barrier such as the median eminence or in a peripheral tissue(s); (3) tryptophan-derived 5-HT can stimulate these receptors, but only if allowed to accumulate by inhibiting its catabolism; and (4) it is not yet clear whether pituitary-adrenal responses to quipazine and 6-MeO-THBC are mediated by a serotonergic mechanism.