Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis.
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.
Guillot
Thomas S
TS
Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA.
Shepherd
Kennie R
KR
Richardson
Jason R
JR
Wang
Min Z
MZ
Li
Yingjie
Y
Emson
Piers C
PC
Miller
Gary W
GW
D019969:Amphetamine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002451:Cell Compartmentation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005334:Fever / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D005911:Gliosis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects* / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000187:drug effects* / Q000235:genetics
D015415:Biomarkers; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D008694:Methamphetamine; D004298:Dopamine