Repeated cocaine exposure inhibits the adrenocorticotropic hormone response to the serotonin releaser d-fenfluramine and the 5-HT1A agonist, 8-OH-DPAT.
The influence of cocaine exposure on serotonergic neurons and postsynaptic 5-HT1A receptor-mediated responses was evaluated by measuring neuroendocrine responses to a serotonin (5-HT) releaser or a 5-HT1A 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-HT1A agonist, 8-OH-DPAT (0, 10, 50, 200 or 500 micrograms/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-HT2A and/or 5-HT2C receptor-mediated responses, the present data suggest that repeated cocaine exposure produces subsensitivity to at least some postsynaptic 5-HT1A receptors. Cocaine-induced deficits in the ACTH response to 5-HT releasers may reflect 5-HT1A receptor subsensitivity, but presynaptic deficits cannot be excluded. Examination of the ACTH response to 5-HT1A agonists may represent a valuable approach to determine deficits in 5-HT function in human cocaine abusers.
Levy
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Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153.
Li
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Van de Kar
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D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D005277:Fenfluramine / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D011388:Prolactin / Q000097:blood; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects; D012083:Renin / Q000097:blood; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects
D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D005473:Fluoxetine; D005277:Fenfluramine; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D012083:Renin; D003042:Cocaine