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Vol. 293, Issue 2, 329-335, May 2000
Department of Neurology, University of Medicine and Dentistry of
New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey
(R.G.W.S., K.A.H., P.K.S.); and Department of Psychiatry, University of
Texas Southwestern Medical Center, Dallas, Texas (C.-L.L., D.C.G.)
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 Km value of
[3H]MPP+ transport was similar in the two
species. In contrast, the maximal transport rate
(Vmax) was 2-fold greater in vesicles from
rats than in those from mice. Likewise, the
Km value for [3H]DA transport
was similar in both preparations, but the
Vmax value was 2-fold greater in rat than in
mouse vesicles. The Bmax 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.
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