Rotenone and CCCP inhibit tyrosine hydroxylation in rat striatal tissue slices

Complex I inhibition has been implicated in the neurotoxicity of MPTP and rotenone, which reproduce a neurochemical and neuropathological feature of Parkinson's disease in experimental animals. Previous studies performed in rat striatal slices have shown that dopaminergic neurotoxins, MPTP and manganese, inhibit tyrosine hydroxylation, a rate-limiting step of dopamine biosynthesis. In this study, we examined the effect of mitochondrial toxins such as rotenone and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on tyrosine hydroxylation in rat striatal slices. Rotenone and CCCP inhibited DOPA formation with an accompanying decrease in ATP and increase in lactate of rat striatal slices during 1 h incubation. Furthermore, rotenone reduced dopamine (DA), dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA) levels in PC12 cells after 20 h incubation. These results suggest that tyrosine hydroxylation is inhibited in dopaminergic neurons soon after exposure to sub-micromolar concentrations of rotenone and CCCP, leading to dopamine depletion.