Abstract

Dopamine neurons from various animal species differ in sensitivity to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP⁺). Compared with striatal vesicles isolated from mice, those from rats have a higher density of the brain vesicular monoamine transporter (VMAT2) and a greater ability to sequester MPP⁺, suggesting a larger storage capacity for MPP⁺ in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide protection against the neurotoxic effects of MPP⁺in vivo. Dose-response curves for striatally infused MPP⁺were determined in animals pretreated with or without a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 inhibitor) produced a 5-fold leftward shift in the MPP⁺ dose-response curve and a significant lowering of the EC₅₀ concentration for MPP⁺-induced damage. These findings provide evidence for a substantial accumulation of MPP⁺ in VMAT2-containing vesicles in vivo in the rat striatum and support the hypothesis that MPP⁺ sequestration in vesicles can provide protection against its toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxicity produced by a striatal infusion of MPP⁺or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP⁺ may be of less importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced striatal MPP⁺ toxicity in the rat, the potency of MPP⁺ in the rat striatum was less than that in mouse striatum. This implies that there are other factors that either exacerbate MPP⁺ toxicity in the mouse or attenuate MPP⁺ toxicity in rats.