Increased striatal dopamine turnover following acute administration of rotenone to mice

Because of the potential role of mitochondrial dysfunction in nigrostriatal degeneration in Parkinson's disease, the effects of rotenone tan inhibitor of mitochondrial NADH dehydrogenase and a naturally occurring toxicant) on the levels of striatal dopamine (DA) and DA metabolites were evaluated aft er acute and subchronic administration to mice. Systemic acute treatment wi th relatively high doses of rotenone did not affect DA concentration, but c aused a significant increase in both DA metabolites, 3,4-dihydroxyphenylace tic acid (DOPAC) and homovanillic acid (HVA). DOPAC and HVA changes were me asured at 1 day and were reversed within 1 week. paralleling the time cours e of rotenone-induced increase in striatal lactate levels. Subchronic admin istration with a relatively mild dose of rotenone did not significantly alt er the striatal levels of DA and DOPAC, while it slightly reduced HVA conce ntration. No neurochemical signs of dopaminergic damage were seen when mice were co-exposed to rotenone and diethyldithiocarbamate, a compound known t o enhance nigrostriatal injury caused by the neurotoxicant 1-methyl-4-pheny l-1,2,3,6-tetrahydropyridine (MPTP). Also, rotenone did not cause additiona l injury to animals previously lesioned by MPTP. Taken together, data indic ate that rotenone is not capable of causing overt dopaminergic toxicity und er the testing paradigms used in this study. Rather, an increase in DA turn over, as indicated by a higher (DOPAC+HVA)/DA ratio, seems to be associated to rotenone-induced striatal energy impairment. (C) 2000 Elsevier Science B.V. All rights reserved.