In an attempt to clarify whether m-chlorophenylpiperazine-(m-CPP) and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-(DOI) induced increases in plasma adrenocorticotropin hormone, corticosterone and prolactin secretion are mediated by the same or different mechanisms, we studied the time course of development of tolerance to the neuroendocrine effects of m-CPP (2.5 mg/kg/day) and DOI (2.5 mg/kg/day) in rats and, furthermore, also evaluated possible cross-tolerance in responses to m-CPP and DOI. We observed the development of tolerance in adrenocorticotropin hormone responses after a single i.p. injection of m-CPP. However, there was no cross-tolerance to DOI when chronic (13 days) m-CPP-treated animals were challenged with DOI (2.5 mg/kg). Injections of DOI (2.5 mg/kg) for six days were required before tolerance developed to the effect of DOI on adrenocorticotropin hormone. Furthermore, cross-tolerance was observed when DOI-treated animals (2.5 mg/kg/day x 6) were challenged with m-CPP (2.5 mg/kg) on day 7. In contrast, daily administration of m-CPP and DOI for 13 days did not produce tolerance to their stimulating effects on corticosterone and prolactin secretion. Hypothalamic levels of 5-hydroxyindoleacetic acid but not 5-HT were significantly reduced after acute or subchronic administration of both m-CPP and DOI. Furthermore, no change in the approximate 50% reduction in 5-hydroxyindoleacetic acid after m-CPP was observed after subchronic administration of this drug. These findings suggest that separate mechanisms mediate m-CPP and DOI-induced adrenocorticotropin hormone secretion in rats.