1-(m-chlorophenyl)piperazine (mCPP) dissociates in vivo serotonin release from long-term serotonin depletion in rat brain

Serotonin (5-HT) releasing agents such as d-fenfluramine are known to cause long-term depletion of forebrain 5-HT in animals, but the mechanism of thi s effect is unknown. In the present study, we examined the relationship bet ween drug-induced 5-HT release and long-term 5-HT depletion in rat brain. T he 5-HT-releasing actions of d-fenfluramine and a non-amphetamine 5-HT drug , 1-(m-chlorophenyl)piperazine (mCPP), were compared using in vivo microdia lysis in the nucleus accumbens. The ability of d-fenfluramine and mCPP to i nteract with 5-HT transporters was tested using in vitro assays for T [H-3] 5-HT uptake and radioligand binding. Local infusion of d-fenfluramine or mC PP (1-100 muM) increased extracellular 5-HT, with elevations in dopamine oc curring at high doses. Intravenous injection of either drug (1-10 mu mol/kg ) produced dose-related increases in 5-HT without affecting dopamine. d-Fen fluramine and mCPP exhibited similar potency in their ability to stimulate 5-HT efflux in vivo and interact with 5-HT transporters in vitro. When rats received high-dose d-fenfluramine or mCPP (10 or 30 mu mol/kg, i.p., every 2 h, 4 doses), only d-fenfluramine-treated rats displayed long-term 5-HT d epletions. Thus, mCPP is a 5-HT releaser that does not appear to cause 5-HT depletion. Our data support the notion that 5-HT release per se may not be sufficient to produce the long-term 5-HT deficits associated with d-fenflu ramine and other amphetamines. (C) 2001 American College of Neuropsychophar macology. Published by Elsevier Science Inc.