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Research ArticleCELLULAR AND MOLECULAR

In Vitro Studies of Striatal Vesicles Containing the Vesicular Monoamine Transporter (VMAT2): Rat versus Mouse Differences in Sequestration of 1-Methyl-4-phenylpyridinium

Roland G. W. Staal, Kelly A. Hogan, Chang-Lin Liang, Dwight C. German and Patricia K. Sonsalla
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 329-335;
Roland G. W. Staal
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Kelly A. Hogan
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Chang-Lin Liang
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Dwight C. German
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Patricia K. Sonsalla
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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 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, theKm value for [3H]DA transport was similar in both preparations, but theVmax 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.

Footnotes

  • Send reprint requests to: Dr. Patricia K. Sonsalla, Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-4535. E-mail: sonsalla{at}umdnj.edu

  • ↵1 This work was supported by National Institutes of Health Grant AG08479 and National Institute of Environmental Health Sciences Grant ES07148. The synthesis and characterization of [3H]DTBZ binding were supported by National Institutes of Health Grants AG08671 and MH47611 to Drs. Michael Kilbourn and Kirk Frey (University of Michigan).

  • Abbreviations:
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    VMAT2
    vesicular monoamine transporter 2
    DAT
    dopamine transporter
    DA
    dopamine
    DTBZ
    dihydrotetrabenazine
    MPP+
    1-methyl-4-phenylpyridinium
    SSV
    small synaptic vesicle
    EM
    electron microscopic (microscope)
    • Received April 6, 1999.
    • Accepted February 14, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleCELLULAR AND MOLECULAR

In Vitro Studies of Striatal Vesicles Containing the Vesicular Monoamine Transporter (VMAT2): Rat versus Mouse Differences in Sequestration of 1-Methyl-4-phenylpyridinium

Roland G. W. Staal, Kelly A. Hogan, Chang-Lin Liang, Dwight C. German and Patricia K. Sonsalla
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 329-335;

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Research ArticleCELLULAR AND MOLECULAR

In Vitro Studies of Striatal Vesicles Containing the Vesicular Monoamine Transporter (VMAT2): Rat versus Mouse Differences in Sequestration of 1-Methyl-4-phenylpyridinium

Roland G. W. Staal, Kelly A. Hogan, Chang-Lin Liang, Dwight C. German and Patricia K. Sonsalla
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 329-335;
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