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Impairment of the mitochondrial complex I has been found in Parkinson's disease and recently long-term treatment with the complex I inhibitor rotenone led to neurodegeneration and Lewy body-like inclusions in rats. To investigate the relationship of free radical formation, complex I inhibition, and dopamine release, rotenone (15 mg/kg s.c.) was injected in male Sprague Dawley rats. Complex I inhibition was measured in the striatum and substantia nigra using the lactate accumulation assay. Dopamine release and free radical formation was determined using striatal microdialysis in combination with the salicylate hydroxylation assay. In a second experiment, glutamate (10 mM) stimulation via the microdialysis probe was used to provoke hydroxyl radical formation and dopamine release 60 min after rotenone or vehicle pretreatment. Rotenone significantly increased striatal and nigral lactate levels. However, rotenone did not produce a significant increase in hydroxyl radical formation and dopamine release, but led to a pronounced hypokinesia. In contrast, rotenone in comparison to vehicle pretreatment produced a significant augmentation of glutamate-induced dopamine release (67-fold and 31-fold increase, respectively) and did not affect the glutamate-induced hydroxyl free radical formation (23-fold and 21-fold increase, respectively). The present study demonstrates that a single systemic rotenone administration does not lead to neurotoxicity, but rather to enhanced glutamate-induced dopamine release with no further increase of hydroxyl free radical formation. Thus, acute complex I inhibition in the presence or absence of high extracellular dopamine and glutamate levels is not critically involved in the formation of hydroxyl free radicals. Synapse 50:240–250, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]