Abstract

Significant differences exist in the sensitivity of mice and rats to the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that cannot be explained by differences in exposure to or uptake of 1-methyl-4-phenylpyridinium (MPP⁺) into dopamine (DA) neurons. MPP⁺ is also a substrate for the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP⁺ toxicity. A greater sequestration of MPP⁺ into vesicles of DA neurons in rats versus mice could explain the lower vulnerability of DA neurons in the rat to MPP⁺ toxicity. To test this hypothesis, the kinetics of uptake for [³H]MPP⁺ and [³H]DA as well as [³H]dihydrotetrabenazine binding to VMAT2 were compared in vesicles isolated from the striata of rats and mice. The K_m value of [³H]MPP⁺ transport was similar in the two species. In contrast, the maximal transport rate (V_max) was 2-fold greater in vesicles from rats than in those from mice. Likewise, theK_m value for [³H]DA transport was similar in both preparations, but theV_max value was 2-fold greater in rat than in mouse vesicles. The B_max value for [³H]dihydrotetrabenazine binding was also 2-fold greater in striatal vesicles from rats than in those from mice. Electron micrographs demonstrated that vesicles isolated from rats and mice were approximately the same size. Based on these observations, we propose that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the reduced vulnerability of rat DA neurons to MPP⁺neurotoxicity.