ALPHA-PHENYL-N-TERT-BUTYL NITRONE ATTENUATES METHAMPHETAMINE-INDUCED DEPLETION OF STRIATAL DOPAMINE WITHOUT ALTERING HYPERTHERMIA

Methamphetamine (MA) administration to adult rats (4 x 10 mg/kg s.c.) induces neurotoxicity predominately characterized by a persistent redu ction of neostriatal dopamine (DA) content. Hyperthermia following MA administration potentiates the resulting DA depletion. DA-derived free radicals are postulated to be a mechanism through which MA-induced ne urotoxicity is produced. The spin trapping agent PEN reacts with free radicals to form nitroxyl adducts, thereby preventing damaging free ra dical reactions with cellular substrates. MA with saline pretreatment (Sal-MA) reduced neostriatal DA by 55% (P < 0.01 vs. Sal-Sal). MA with PEN pretreatment (PBN-MA) at 36 or 60 mg/kg reduced neostriatal DA by 36 and 22%, respectively (P < 0.05 and P < 0.01 vs. Sal-MA) indicatin g partial protection. PEN pretreatment did not alter MA-induced hypert hermia. Thus, PEN does not attenuate MA-induced neurotoxicity by reduc ing MA-induced hyperthermia. These results support a role for free rad icals in the generation of MA-induced dopaminergic neurotoxicity. (C) 1996 Wiley-Liss, Inc.