Methamphetamine-induced Selective Dopaminergic Neurotoxicity Is Accompanied by an Increase in Striatal Nitrate in the Mouse

Ann N Y Acad Sci. 2006 Aug;1074:225-33. doi: 10.1196/annals.1369.021.

Abstract

Exposure to high doses of methamphetamine (METH), a major drug of abuse, may cause neuronal damage. Previous studies have implicated the role of peroxynitrite, produced by nitric oxide (NO) and reactive oxygen species, in dopaminergic neurotoxicity produced by METH in mice. The present article was undertaken to investigate if a neurotoxic regimen of METH is associated with changes in tissue levels of nitrate and nitrite, which are the stable products of NO. Administration of METH (5 mg/kg x 3) to Swiss Webster mice resulted in marked depletion of dopamine (DA) and DA transporter (DAT) binding sites but no change in 5-hydroxytryptamine (5-HT) and 5-HT transporter (5-HTT) binding sites in the striatum, amygdala, frontal cortex, and hippocampus, suggesting that METH causes selective neurotoxicity to DA nerve terminals. The concentration of nitrate in the striatum was increased by about two-fold after METH administration; however, no changes in nitrate concentration were detected in other brain regions that endured dopaminergic neurotoxicity. These findings suggest that (a) a neurotoxic regimen of METH produces selective increase in NO in the striatum, which may generate toxic species such as peroxynitrite, and (b) toxins other than NO-related derivatives may mediate dopaminergic neurotoxicity in the amygdala and frontal cortex.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism*
  • Corpus Striatum / metabolism*
  • Dopamine / analysis
  • Dopamine Agents / toxicity
  • Dopamine Plasma Membrane Transport Proteins / analysis
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Male
  • Methamphetamine / toxicity*
  • Mice
  • Nitrates / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide / physiology*
  • Serotonin / analysis
  • Serotonin / metabolism

Substances

  • Dopamine Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Nitrates
  • Nitric Oxide
  • Serotonin
  • Methamphetamine
  • Dopamine