STUDIES ON SPECIES SENSITIVITY TO THE DOPAMINERGIC NEUROTOXIN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE .2. CENTRAL ADMINISTRATION OF 1-METHYL-4-PHENYLPYRIDINIUM

There are marked species differences in susceptibility to the neurotox ic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mic e are sensitive, whereas rats are relatively insensitive to MPTP. In t hese two species, the effects of peripherally administered MPTP or int rastriatally infused 1-methyl-4-phenylpyridinium (MPP(+)) were examine d to identify potential underlying mechanisms responsible for their di fference in susceptibility to MPTP. In vivo intrastriatal microdialysi s and an MPP(+) 2-day test/challenge paradigm were used to monitor dop amine efflux as an indicator of the neurotoxic effects of MPTP or MPP( +). By using this method, the EC(50) for neurotoxicity by an intrastri atal infusion of MPP(+) in mice was 0.4 mM, whereas it was 10-fold hig her in rats (4.3 mM). In addition, by using the traditional postmortem examination, neostriatal dopamine was depleted markedly in mice (grea ter than or equal to 80%), but only depleted marginally in rats in whi ch MPP(+) was infused into the neostriatum. These data indicate that r ats are relatively insensitive to MPTP as compared to mice, because th ey are less sensitive to MPP(+) whether it is formed in vivo from MPTP administered systemically or administered directly into neostriata. T hus, there appears to be a fundamental difference in the susceptibilit y of the nigrostriatal systems in these two species to the neurotoxic consequences of MPP(+) exposure.