Intra-striatal infusion of D-amphetamine induces hydroxyl radical formation: inhibition by MK-801 pretreatment

Recent evidence suggests that free radicals can be produced in the brain fo llowing systemic administration of repeated or high doses of D-amphetamine (AMPH), However, it has been proposed that the toxic effects of AMPH are mo stly secondary to AMPH-induced hyperthermia, and agents that protect agains t AMPH neurotoxicity do so by blocking AMPH-induced hyperthermia or causing hypothermia. In this study, we examined the effects of AMPH on the formati on of hydroxyl radicals ((OH)-O-.) following its infusion into the rat stri atum via a microdialysis probe, We found that intra-striatal perfusion of A MPH (10 mu M) caused an increased formation of hydroxyl radicals but did no t raise the core temperatures of the rats. Pretreatment with the NMDA antag onist MK-801 (0.5 mg/kg) attenuated hydroxyl radical production elicited by AMPH infusion, although core body temperatures in AMPH-treated rats were n ot significantly altered. Additionally, infusion of AMPH in the striatum in creased extracellular dopamine concentration and this effect was potentiate d by MK-801 pretreatment, Thus, these results demonstrate that direct infus ion of AMPH in the striatum induces hydroxyl radical production without cau sing hyperthermia, and also imply that activation of glutamate NMDA recepto rs mediates, at least in part, AMPH-induced hydroxyl radical formation in t he rat striatum. (C) 2000 Elsevier Science Ltd. All rights reserved.