Vol. 293, Issue 2, 336-342, May 2000

Inhibition of Brain Vesicular Monoamine Transporter (VMAT2) Enhances 1-Methyl-4-phenylpyridinium Neurotoxicity In Vivo in Rat Striata¹

Roland G. W. Staal and Patricia K. Sonsalla

Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey

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.