THE EFFECT OF N-METHYLATION ON FENFLURAMINES NEUROTOXIC AND PHARMACOLOGICAL ACTIONS

N-Methylation separates methamphetamine's neurotoxic and pharmacologic effects. In particular, N-methylation eliminates methamphetamine's ne urotoxic activity while preserving its behavioral pharmacologic activi ty. The purpose of the present studies was to determine whether N-meth ylation could also be used to separate fenfluramine's neurotoxic and p harmacologic effects. Fenfluramine-induced serotonin neurotoxicity was assessed by measuring serotonin axonal markers 2 weeks after fenflura mine administration. Pharmacologic effects of fenfluramine were assess ed by measuring fenfluramine-induced anorexia and fenfluramine discrim ination. Both fenfluramine and its N-methylated analog, N-methylfenflu ramine, produced dose-related effects in food intake, drug-discriminat ion and neurotoxicity studies. Although N-methylation reduced the neur otoxic potency of fenfluramine, it also reduced its pharmacologic acti vity. Neurotoxic potency was reduced 4- to 8-fold (depending on brain region), while pharmacologic potency was reduced 4- to 10-fold (depend ing on paradigm). Notably, N-methylation did not change the efficacy o f fenfluramine as a serotonin neurotoxin, anorectic agent or discrimin ation stimulus. These results indicate that fenfluramine's behavioral and neurotoxic effects, unlike those of methamphetamine, are not disso ciated by N-methylation. Further, the present results suggest that the effectiveness of side-chain nitrogen substitution in separating the b ehavioral and neurotoxic effects of amphetamine derivatives is strongl y influenced by ring substitutions. (C) 1997 Elsevier Science B.V.