Amphetamine increases glutamate efflux in the rat ventral tegmental area by a mechanism involving glutamate transporters and reactive oxygen species

Marina E. Wolf, Chang Jiang Xue, Yong Li, David Wavak

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We have shown that amphetamine produces a delayed and sustained increase in glutamate levels in the ventral tegmental area, a region containing dopamine cell bodies important in acute and chronic effects of amphetamine administration. The present study characterized the mechanism underlying amphetamine-induced glutamate efflux. It was abolished by the glutamate uptake inhibitor dihydrokainate, but unaffected by perfusion with a low Ca2+/high Mg2+ solution, implicating glutamate transporters. Because reactive oxygen species inhibit glutamate uptake, we examined the effect of amphetamine on hydroxyl radical formation by perfusing with D-phenylalanine (5 mM) and monitoring p-tyrosine production. Although no increase in hydroxyl radical formation was detected, D-phenylalanine completely prevented the amphetamine-induced increase in glutamate efflux, as did systemic injection of another trapping agent, α-phenyl-N-tert-butyl nitrone (60 mg/kg). Thus, amphetamine-induced glutamate efflux may involve reactive oxygen species. In other studies, we found that repeated coadministration of α-phenyl-N-tert-butyl nitrone with amphetamine attenuated the development of behavioral sensitization. This supports prior results indicating that the increase in glutamate efflux produced by each amphetamine injection in a chronic regimen is important in triggering drug-induced adaptations in ventral tegmental area dopamine neurons, and that such adaptations may in part represent a response to metabolic and oxidative stress.

Original languageEnglish (US)
Pages (from-to)1634-1644
Number of pages11
JournalJournal of Neurochemistry
Issue number4
StatePublished - Sep 26 2000



  • Amphetamine
  • Glutamate uptake
  • Microdialysis
  • Reactive oxygen species
  • Ventral tegmental area
  • α-Phenyl-N-tert-butyl nitrone

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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