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 1h 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.