Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis

Authors

  • Thomas S. Guillot,

    1. Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA
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  • Kennie R. Shepherd,

    1. Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA
    2. Department of Environmental and Occupational Health, Rollins School of Public Health, Atlanta, Georgia, USA
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  • Jason R. Richardson,

    1. Department of Environmental and Occupational Medicine, Environmental and Occupational Health Sciences Institute, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
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  • Min Z. Wang,

    1. Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA
    2. Department of Environmental and Occupational Health, Rollins School of Public Health, Atlanta, Georgia, USA
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  • Yingjie Li,

    1. Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA
    2. Department of Environmental and Occupational Health, Rollins School of Public Health, Atlanta, Georgia, USA
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  • Piers C. Emson,

    1. Department of Neurobiology, the Babraham Institute, Cambridge, UK
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  • Gary W. Miller

    1. Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA
    2. Department of Environmental and Occupational Health, Rollins School of Public Health, Atlanta, Georgia, USA
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Address correspondence and reprint requests to Gary W. Miller, Whitehead Biomedical Research Building 505K, 615 Michael Street, Atlanta, GA 30322, USA. E-mail: gary.miller@emory.edu

Abstract

The vesicular monoamine transporter 2 (VMAT2) controls the loading of dopamine (DA) into vesicles and therefore determines synaptic properties such as quantal size, receptor sensitivity, and vesicular and cytosolic DA concentration. Impairment of proper DA compartmentalization is postulated to underlie the sensitivity of DA neurons to oxidative damage and degeneration. It is known that DA can auto-oxidize in the cytosol to form quinones and other oxidative species and that this production of oxidative stress is thought to be a critical factor in DA terminal loss after methamphetamine (METH) exposure. Using a mutant strain of mice (VMAT2 LO), which have only 5–10% of the VMAT2 expressed by wild-type animals, we show that VMAT2 is a major determinant of METH toxicity in the striatum. Subsequent to METH exposure, the VMAT2 LO mice show an exacerbated loss of dopamine transporter and tyrosine hydroxylase (TH), as well as enhanced astrogliosis and protein carbonyl formation. More importantly, VMAT2 LO mice show massive argyrophilic deposits in the striatum after METH, indicating that VMAT2 is a regulator of METH-induced neurodegeneration. The increased METH neurotoxicity in VMAT2 LO occurs in the absence of any significant difference in basal temperature or METH-induced hyperthermia. Furthermore, primary midbrain cultures from VMAT2 LO mice show more oxidative stress generation and a greater loss of TH positive processes than wild-type cultures after METH exposure. Elevated markers of neurotoxicity in VMAT2 LO mice and cultures suggest that the capacity to store DA determines the amount of oxidative stress and neurodegeneration after METH administration.

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