Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT

MDMA-induced 5-HT neurotoxicity has been proposed to involve oxidative stre ss due to increased formation of hydroxyl radicals. Recently, MDMA-induced 5-HT neurotoxicity has been shown to be accompanied by a suppression of beh avioral and neurochemical responses to a subsequent injection of MDMA. The intent of the present study was to examine whether suppression of the MDMA- induced formation of hydroxyl radicals by an antioxidant, ascorbic acid, at tenuates both the MDMA-induced depletion of 5-HT and the functional consequ ences associated with this depletion. Treatment of rats with ascorbic acid suppressed the generation of hydroxyl radicals, as evidenced by the product ion of 2,3-dihydroxybenzoic acid from salicylic acid, in the striatum durin g the administration of a neurotoxic regimen of MDMA. Ascorbic acid also at tenuated the MDMA-induced depletion of striatal 5-HT content. In rats treat ed with a neurotoxic regimen of MDMA, the ability of a subsequent injection of MDMA to increase the extracellular concentration of 5-HT in the striatu m, elicit the 5-HT behavioral syndrome, and produce hyperthermia was marked ly reduced compared to the responses in control rats. The concomitant admin istration of ascorbic acid with the neurotoxic regimen of MDMA prevented th e diminished neurochemical and behavioral responses to a subsequent injecti on of MDMA. Finally, a neurotoxic regimen of MDMA produced significant redu ctions in the concentrations of vitamin E and ascorbic acid in the striatum and hippocampus. Thus, the MDMA-induced depletion of brain 5-HT and the fu nctional consequences thereof appear to involve the induction of oxidative stress resulting from an increased generation of free radicals and diminish ed antioxidant capacity of the brain. (C) 2001 Wiley-Liss. Inc.