Inhibition of tyrosine hydroxylation in tissue slices of the rat striatum by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a nigrostriatal neurotoxin in humans and primates, at 10(-5) M inhibited hydroxylation of tyrosine to 3,4-dihydrophenylalanine (DOPA), the rate-limiting step of dopamine synthesis, in tissue slices of the striatum and nucleus accumbens of the rat. Nomifensine, an inhibitor of dopamine uptake, reversed the inhibition but sulpiride, a dopamine receptor antagonist, did not affect the inhibition. MPTP at 10(-5) M inhibited neither the purified tyrosine hydroxylase nor dihydropteridine reductase in vitro. The level of total biopterin did not change significantly, but the tetrahydrobiopterin level was decreased in the striatal slices incubated in the presence of MPTP. These results suggest that MPTP inhibits dopamine synthesis in situ at the tyrosine hydroxylase step probably through inhibition of dihydropteridine reductase.