Uptake inhibition protects nigro-striatal dopamine neurons from the neurotoxicity of 1-methyl-4-phenylpyridine (MPP+) in mice.

Intracerebroventricular administration of MPP+ to C57 BL/6 mice caused a pronounced depletion of striatal levels of dopamine and 3,4-dihydroxyphenyl-acetic acid ipsilaterally, and a less marked depletion contralaterally. The MPP+-induced reductions were clearly diminished by pretreatment with the dopamine uptake inhibitors mazindol and nomifensine. Similar results were obtained from determinations using tyrosine hydroxylase immunohistochemistry. These results are consistent with the hypothesis that MPTP neurotoxicity is related to the formation of MPP+ from MPTP outside the dopamine neurons and that subsequent uptake of MPP+ into these neurons initiates degeneration.