RT Journal Article
SR Electronic
T1 Inhibition of Brain Vesicular Monoamine Transporter (VMAT2) Enhances 1-Methyl-4-phenylpyridinium Neurotoxicity In Vivo in Rat Striata
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 336
OP 342
VO 293
IS 2
A1 Staal, Roland G. W.
A1 Sonsalla, Patricia K.
YR 2000
UL http://jpet.aspetjournals.org/content/293/2/336.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics