Malonate-induced generation of reactive oxygen species in rat striatum depends on dopamine release but not on NMDA receptor activation

Intrastriatal injection of the reversible succinate dehydrogenase inhibitor malonate produces both energy depletion and striatal lesions similar to th at seen in cerebral ischemia and Huntington's disease. The mechanisms of ne uronal cell death involve secondary excitotoxicity and the generation of re active oxygen species. Here, we investigated the effects of dopamine on mal onate-induced generation of hydroxyl radicals and striatal lesion volumes. Using in vivo microdialysis, we found that malonate induced a 94-fold incre ase in extracellular striatal dopamine concentrations. This was paralleled by an increase in the generation of hydroxyl radicals. Prior unilateral les ioning of the nigrostriatal dopaminergic pathway by focal injection of 6-hy droxydopamine blocked the malonate-induced increase in dopamine concentrati ons and the generation of hydroxyl radicals acid attenuated the lesion volu me. In contrast, the NMDA receptor antagonist MK-801 attenuated malonate-in duced lesion volumes but did not block the generation of hydroxyl radicals. Thus, the dopaminergic and glutamatergic pathways are essential in the pat hogenesis of malonate-induced striatal lesions. Our results suggest that th e malonate-induced release of dopamine but not NMDA receptor activation med iates hydroxyl radical formation.