Repeated cocaine exposure inhibits the adrenocorticotropic hormone response to the serotonin releaser d-fenfluramine and the 5-HT_1A agonist, 8-OH-DPAT

The influence of cocaine exposure on serotonergic neurons and postsynaptic 5-HT_1A receptor-mediated responses was evaluated by measuring neuroendocrine responses to a serotonin (5-HT) releaser or a 5-HT_1A agonist. Male rats received cocaine (15 mg/kg, i.p.) or saline twice daily for 7 days. Forty-two hr after the final cocaine injection, the 5-HT releaser d-fenfluramine (0, 0.2, 0.6, 2, or 5 mg/kg, i.p.) or the 5-HT_1A agonist, 8-OH-DPAT (0, 10, 50, 200 or 500 μg/kg, s.c.) were administered. Blood samples were then collected for analysis of plasma ACTH, prolactin, and renin concentrations. The ACTH responses to d-fenfluramine and 8-OH-DPAT were inhibited in cocaine pretreated rats. However, the prolactin responses to d-fenfluramine and 8-OH-DPAT were not significantly modified by cocaine exposure. Additionally, the renin response to d-fenfluramine was unaltered by repeated cocaine administration, while 8-OH-DPAT did not alter renin secretion in either pretreatment group. In contrast to published reports which show that cocaine exposure produces supersensitive 5-HT_2A and/or 5-HT_2C receptor-mediated responses, the present data suggest that repeated cocaine exposure produces subsensitivity to at least some postsynaptic 5-HT_1A receptors. Cocaine-induced deficits in the ACTH response to 5-HT releasers may reflect 5-HT_1A receptor subsensitivity, but presynaptic deficits cannot be excluded. Examination of the ACTH response to 5-HT_1A agonists may represent a valuable approach to deermine deficits in 5-HT function in human cocaine abusers.