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

J Neurochem. 2000 Oct;75(4):1634-44. doi: 10.1046/j.1471-4159.2000.0751634.x.


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 Ca(2+)/high Mg(2+) 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, alpha-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 alpha-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

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism*
  • Amino Acid Transport System X-AG
  • Amphetamine / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Calcium / metabolism
  • Calcium / pharmacology
  • Central Nervous System Stimulants / pharmacology
  • Cyclic N-Oxides
  • Free Radical Scavengers / pharmacology
  • Glutamic Acid / metabolism*
  • Hydroxyl Radical / metabolism
  • Male
  • Microdialysis
  • Motor Activity / drug effects
  • Neuroprotective Agents / pharmacology
  • Nitrogen Oxides / pharmacology
  • Phenylalanine / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism*
  • Tyrosine / biosynthesis
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism


  • ATP-Binding Cassette Transporters
  • Amino Acid Transport System X-AG
  • Central Nervous System Stimulants
  • Cyclic N-Oxides
  • Free Radical Scavengers
  • Neuroprotective Agents
  • Nitrogen Oxides
  • Reactive Oxygen Species
  • Hydroxyl Radical
  • phenyl-N-tert-butylnitrone
  • Glutamic Acid
  • Tyrosine
  • Phenylalanine
  • Amphetamine
  • Calcium