期刊
JOURNAL OF NEUROCHEMISTRY
卷 75, 期 4, 页码 1634-1644出版社
WILEY
DOI: 10.1046/j.1471-4159.2000.0751634.x
关键词
amphetamine; glutamate uptake; microdialysis; alpha-phenyl-N-tert-butyl nitrone; reactive oxygen species; ventral tegmental area
资金
- NIDA NIH HHS [DA00453, DA09621] Funding Source: Medline
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, 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.
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