Inhibition of brain vesicular monoamine transporter (VMAT2) enhances 1-methyl-4-phenylpyridinium neurotoxicity in vivo in rat striata

Dopamine neurons from various animal species differ in sensitivity to the n eurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-me thyl-4-phenylpyridinium (MPP+). Compared with striatal vesicles isolated fr om mice, those from rats have a higher density of the brain vesicular monoa mine transporter (VMAT2) and a greater ability to sequester MPP+, suggestin g a larger storage capacity for MPP+ in rat vesicles. In the present study, we examined whether striatal VMAT2-containing vesicles might provide prote ction against the neurotoxic effects of MPP+ in vivo. Dose-response curves for striatally infused MPP+ were determined in animals pretreated with or w ithout a VMAT2 inhibitor. Ro 4-1284 administration (10 mg/kg i.p.; VMAT2 in hibitor) produced a 5-fold leftward shift in the MPP+ dose-response curve a nd 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 hypo thesis that MPP+ sequestration in vesicles can provide protection against i ts toxic actions. In mice, VMAT2 inhibition did not reliably enhance toxici ty produced by a striatal infusion of MPP+ or by systemic administration of MPTP. These data suggest that vesicular sequestration of MPP+ may be of le ss importance in mice than in rats as relates to protection from the toxin. The present results also reveal that although VMAT2 inhibition enhanced st riatal MPP+ toxicity in the rat, the potency of MPP+ in the rat striatum wa s less than that in mouse striatum. This implies that there are other facto rs that either exacerbate MPP+ toxicity in the mouse or attenuate MPP+ toxi city in rats.