A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine.
Methamphetamine (METH) produces long-term decreases in markers of dopamine (DA) terminals in animals and humans. A decrease in the function of the vesicular monoamine transporter 2 (VMAT2) has been associated with damage to striatal DA terminals caused by METH; however, a possible mechanism for this decrease in VMAT2 function has not been defined. The current study showed that METH caused a rapid decrease to 68% of controls in VMAT2 protein immunoreactivity of the vesicular fraction from striatal synaptosomes within 1 h after a repeated high-dose administration regimen of METH. This decrease was associated with a 75% increase in nitrosylation of VMAT2 protein in the synaptosomal fraction as measured by nitrosocysteine immunoreactivity of VMAT2 protein. The rapid decreases in VMAT2 persisted when evaluated 7 days later and were illustrated by decreases in VMAT2 immunoreactivity and DA content of the vesicular fraction to 34% and 51% of control values, respectively. The decreases were blocked or attenuated by prior injections of the neuronal nitric oxide synthase inhibitor, S-methyl-l-thiocitrulline. These studies demonstrate that METH causes a rapid neuronal nitric oxide synthase-dependent oxidation of VMAT2 and long-term decreases in VMAT2 protein and function. The results also suggest that surviving DA terminals after METH exposure may have a compromised capacity to buffer cytosolic DA concentrations and DA-derived oxidative stress.
Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.
David J
DJ
Eyerman
Bryan K
BK
Yamamoto
D000661:Amphetamine / Q000633:toxicity*; D019969:Amphetamine-Related Disorders / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D002021:Buffers; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes; D050493:Vesicular Monoamine Transport Proteins / Q000187:drug effects* / Q000378:metabolism*
D002021:Buffers; D018765:Dopamine Uptake Inhibitors; C493454:Slc18a2 protein, rat; D050493:Vesicular Monoamine Transport Proteins; D000661:Amphetamine; D052248:Nitric Oxide Synthase Type I; D004298:Dopamine