Dopamine Transporter Is Required for In Vivo MPTP Neurotoxicity: Evidence from Mice Lacking the Transporter

Authors

  • Raul R. Gainetdinov,

    1. Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.
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    • Dr. R. R. Gainetdinov is a visiting fellow from the Institute of Pharmacology, Baltiyskaya, 8, 125315, Moscow, Russia.

  • Fabio Fumagalli,

    1. Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.
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    • Dr. F. Fumagalli is a visiting fellow from the Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.

  • Sara R. Jones,

    1. Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.
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  • Marc G. Caron

    Corresponding author
    1. Howard Hughes Medical Institute Laboratories, Department of Cell Biology and Medicine, Duke University Medical Center, Durham, North Carolina, U.S.A.
      Address correspondence and reprint requests to Dr. M. G. Caron at Howard Hughes Medical Institute, Box 3287, Duke University Medical Center, Durham, NC 27710, U.S.A.
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Address correspondence and reprint requests to Dr. M. G. Caron at Howard Hughes Medical Institute, Box 3287, Duke University Medical Center, Durham, NC 27710, U.S.A.

Abstract

Abstract: The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT−/− mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., b.i.d.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT−/− mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+; 10 mM), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT−/− mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo.

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