Amphetamine Increases Glutamate Efflux in the Rat Ventral Tegmental Area by a Mechanism Involving Glutamate Transporters and Reactive Oxygen Species

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 m M ) 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