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 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
Wolf
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ME
Department of Neuroscience, FUHS/The Chicago Medical School, North Chicago, Illinois 60064-3095, USA. marina.wolf@finchcms.edu
Xue
C J
CJ
Li
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Y
Wavak
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D
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027322:Amino Acid Transport System X-AG; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D017665:Hydroxyl Radical / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009589:Nitrogen Oxides / Q000494:pharmacology; D010649:Phenylalanine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014443:Tyrosine / Q000096:biosynthesis; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D000697:Central Nervous System Stimulants; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D017665:Hydroxyl Radical; C029217:phenyl-N-tert-butylnitrone; D018698:Glutamic Acid; D014443:Tyrosine; D010649:Phenylalanine; D000661:Amphetamine; D002118:Calcium