A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine

J Neurochem. 2007 Nov;103(3):1219-27. doi: 10.1111/j.1471-4159.2007.04837.x. Epub 2007 Aug 7.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amphetamine / toxicity*
  • Amphetamine-Related Disorders / metabolism*
  • Amphetamine-Related Disorders / physiopathology
  • Animals
  • Brain / drug effects*
  • Brain / metabolism*
  • Brain / physiopathology
  • Buffers
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiopathology
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dopamine / metabolism
  • Dopamine Uptake Inhibitors / toxicity
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Male
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Synaptosomes
  • Vesicular Monoamine Transport Proteins / drug effects*
  • Vesicular Monoamine Transport Proteins / metabolism*


  • Buffers
  • Dopamine Uptake Inhibitors
  • Slc18a2 protein, rat
  • Vesicular Monoamine Transport Proteins
  • Amphetamine
  • Nitric Oxide Synthase Type I
  • Dopamine