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 dopami ne cell bodies important in acute and chronic effects of amphetamine admini stration. The present study characterized the mechanism underlying amphetam ine-induced glutamate efflux, It was abolished by the glutamate uptake inhi bitor dihydrokainate, but unaffected by perfusion with a low Ca2+/high Mg2 solution, implicating glutamate transporters. Because reactive oxygen spec ies inhibit glutamate uptake, we examined the effect of amphetamine on hydr oxyl radical formation by perfusing with D-phenylalanine (5 mM) and monitor ing p-tyrosine production. Although no increase in hydroxyl radical formati on was detected, D-phenylalanine completely prevented the amphetamine-induc ed increase in glutamate efflux, as did systemic injection of another trapp ing agent, alpha-phenyl-N-tert-butyl nitrone (60 mg/kg), Thus, amphetamine- induced glutamate efflux may involve reactive oxygen species. In other stud ies, we found that repeated coadministration of alpha-phenyl-N-tert-butyl n itrone with amphetamine attenuated the development of behavioral sensitizat ion. This supports prior results indicating that the increase in glutamate efflux produced by each amphetamine injection in a chronic regimen is impor tant in triggering drug-induced adaptations in ventral tegmental area dopam ine neurons, and that such adaptations may in part represent a response to metabolic and oxidative stress.