Attenuation of MPTP-induced dopaminergic neurotoxicity by a serotonin uptake blocker.

Monoamine oxidase-B (MAO-B) has been determined to be the enzyme responsible for the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into its toxic metabolite 1-methyl-4-phenylpyridine ion (MPP+). Since this enzyme has been localized primarily in astrocytes and serotonergic neurons, it would appear that MPP+ is being produced outside the dopaminergic neurons. To investigate this possibility, the administration of MPTP was preceded by systemically administered fluoxetine. In keeping with its demonstrated ability to inhibit uptake into serotonergic neurons and serotonin uptake into astrocytes, fluoxetine pretreatment resulted in a significant attenuation of MPTP-induced depletions of striatal dopamine and serotonin concentration. These results support the extra-dopaminergic production of MPP+.