Histochemical localization of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine oxidation in the mouse brain

The sites in the mouse brain where 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine can be oxidized to the toxic metabolite 1-methyl-4-phenylpyridine were determined using a histochemical technique. The method involved the demonstration of monoamine oxidase activity using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as the substrate by means of a sensitive coupled peroxidase technique. The distribution of neurons displaying the ability to oxidize 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine via a monoamine oxidase catalysed reaction was compared to that of various amine systems identified with immunohistochemistry. Dopamine neurons, and in particular the nigrostriatal dopamine cells, did not display the capacity to oxidize 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Noradrenergic neurons showed intense monoamine oxidase activity when 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was used as substrate, and this activity was blocked by the monoamine oxidase-A inhibitor clorgyline. Serotonin neurons and histamine neurons were also able to oxidize 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The reaction in these neurons was blocked by deprenyl, an inhibitor of monoamine oxidase-B. Pretreatment with inhibitors of monoamine oxidase-B has been previously shown to prevent the neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on dopaminergic neurons. Therefore, since serotonin and histamine neurons are able to oxidize 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by means of monoamine oxidase-B, these neurons may be involved in the production of the toxic metabolites of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in vivo.