Methamphetamine-induced inhibition of mitochondrial complex II: Roles of glutamate and peroxynitrite

Jeffrey M. Brown, Maria S. Quinton, Bryan K. Yamamoto

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

High-dose methamphetamine (METH) is associated with long-term deficits in dopaminergic systems. Although the mechanism(s) which contributes to these deficits is not known, glutamate and peroxynitrite are likely to play a role. These factors are hypothesized to inhibit mitochondrial function, increasing the free radical burden and decreasing neuronal energy supplies. Previous studies suggest a role for the mitochondrial electron transport chain (ETC) in mediating toxicity of METH. The purpose of the present studies was to determine whether METH administration selectively inhibits complex II of the ETC in rats. High-dose METH administration (10 mg/kg every 2 h × 4) rapidly (within 1 h) decreased complex II (succinate dehydrogenase) activity by ∼20-30%. In addition, decreased activity of complex II-III, but not complex I-III, of the mitochondrial ETC was also observed 24 h after METH. This inhibition was not due to direct inhibition by METH or METH-induced hyperthermia and was specific to striatal brain regions. METH-induced decreases in complex II-III were prevented by MK-801 and the peroxynitrite scavenger 5,10,15,20-tetrakis (2,4,6-trimethyl-3,5-sulphonatophenyl) porphinato iron III. These findings provide the first evidence that METH administration, via glutamate receptor activation and peroxynitrite formation, selectively alters a specific site of the ETC.

Original languageEnglish (US)
Pages (from-to)429-436
Number of pages8
JournalJournal of Neurochemistry
Volume95
Issue number2
DOIs
StatePublished - Oct 1 2005
Externally publishedYes

Keywords

  • Electron transport chain
  • Free radicals
  • Mitochondria
  • Neurodegeneration
  • Peroxynitrite
  • Succinate dehydrogenase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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