Dopaminergic Neurotoxicity of 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine in Mice

TLDR

MPTP irreversibly destroys the dopaminergic nigrostriatal pathway and induces parkinsonism in humans and monkeys, but has minimal or no effect in several other animal species. The study aims to establish the mouse as a useful small animal model for investigating MPTP’s mode of action. In mice, 30 mg/kg MPTP reduced striatal dopamine and its metabolites, impaired dopamine uptake, and ablated substantia nigra neurons, while sparing serotonin, mirroring the biochemical and histological changes seen in humans and monkeys with Parkinson’s disease.

Abstract

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is known to cause an irreversible destruction of the dopaminergic nigrostriatal pathway and symptoms of parkinsonism in humans and in monkeys. However, MPTP has been reported to act only minimally or not at all in several other animal species. When MPTP (30 milligrams per kilogram of body weight) was administered parenterally to mice, a decrease in concentrations of neostriatal dopamine and its metabolites, a decrease in the capacity of neostriatal synaptosomal preparations to accumulate [ 3 H]dopamine, and a disappearance of nerve cells in the zona compacta of the substantia nigra were observed. In contrast, MPTP administration had no effect on neostriatal concentrations of serotonin and its metabolites. MPTP administration thus results in biochemical and histological changes in mice similar to those reported in humans and monkeys and similar to those seen in Parkinson's disease in humans. The mouse should prove to be a useful small animal with which to study the mode of action of MPTP.