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Research ArticleCELLULAR AND MOLECULAR

Inhibition of Brain Vesicular Monoamine Transporter (VMAT2) Enhances 1-Methyl-4-phenylpyridinium Neurotoxicity In Vivo in Rat Striata

Roland G. W. Staal and Patricia K. Sonsalla
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 336-342;
Roland G. W. Staal
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Patricia K. Sonsalla
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Abstract

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.

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.

  • Abbreviations:
    MPTP
    1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    VMAT1
    vesicular monoamine transporter 1
    VMAT2
    vesicular monoamine transporter 2
    DA
    dopamine
    DOPAC
    3,4-dihydroxyphenylacetic acid
    HVA
    homovanillic acid
    TH
    tyrosine hydroxylase
    MPP+
    1-methyl-4-phenylpyridinium
    i.s.
    intrastriatal
    WT
    wild-type
    • 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

Inhibition of Brain Vesicular Monoamine Transporter (VMAT2) Enhances 1-Methyl-4-phenylpyridinium Neurotoxicity In Vivo in Rat Striata

Roland G. W. Staal and Patricia K. Sonsalla
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 336-342;

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Research ArticleCELLULAR AND MOLECULAR

Inhibition of Brain Vesicular Monoamine Transporter (VMAT2) Enhances 1-Methyl-4-phenylpyridinium Neurotoxicity In Vivo in Rat Striata

Roland G. W. Staal and Patricia K. Sonsalla
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 336-342;
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