Methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice

Previous studies have suggested a role for the retrograde messenger, nitric oxide (NO), in methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine (MPTP)- induced dopaminergic neurotoxicity. Since evidence su pported the involvement of the neuronal nitric oxide synthase (nNOS) isofor m in the dopaminergic neurotoxicity, the present study was undertaken to in vestigate whether the inducible nitric oxide synthase (iNOS) isoform is als o associated with METH- and MPTP-induced neurotoxicity. The administration of METH (5mg/kg x 3) to iNOS deficient mice [homozygote iNOS(-/-)] and wild type mice (C57BL/6) resulted in significantly smaller depletion of striata l dopaminergic markers in the iNOS(-/-) mice compared with the wild-type mi ce. METH-induced hyperthermia was also significantly lower in the iNOS(-/-) mice than in wild-type mice. In contrast to the outcome of METH administra tion, MPTP injections (20 mg/kg x 3) resulted in a similar decrease in stri atal dopaminergic markers in iNOS(-/-) and wild-type mice. In the set of be havioral experiments, METH-induced locomotor sensitization was investigated . The acute administration of METH (1.0 mg/kg) resulted in the same intensi ty of locomotor activity in iNOS(-/-) and wild-type mice. Moreover, 68 to 7 2 h after the exposure to the high-dose METH regimen (5 mg/kg x 3), a marke d sensitized response to a challenge injection of METH (1.0 mg/kg) was obse rved in both the iNOS(-/-) and wild-type mice. The finding that iNOS(-/-) m ice were unprotected from MPTP-induced neurotoxicity suggests that the part ial protection against METH-induced neurotoxicity observed was primarily as sociated with the diminished hyperthermic effect of METH seen in the iNOS(- /-) mice. Moreover, in contrast to nNOS deficiency, iNOS deficiency did not affect METH-induced behavioral sensitization. (C) 1999 Wiley-Liss, Inc.