The neurotoxin 1-methyl-4-phenylpyridinium is sequestered within neurons that contain the vesicular monoamine transporter

Abstract

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces a parkinsonian syndrome in man and experimental animals. The toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phenylpyridinium, exhibits high-affinity uptake by plasma membrane monoamine transporters and also by the vesicular monoamine transporter. Using autoradiographic and immunohistochemical methods in mice, we demonstrate the accumulation of [³H]1-methyl-4-phenylpyridinium within neurons that contain the vesicular monoamine transporter, following systemic administration of [³H]1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Within 1–24 h following the intraperitoneal administration of 10 μg/kg of [³H]1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, [³H]1-methyl-4-phenylpyridine labelling was found within such regions as the locus coeruleus, dorsal, medial, and pallidal raphe nuclei, substantia nigra pars compacta, ventral tegmental area, and paraventricular nucleus of the hypothalamus. These regions all contain monoaminergic somata as defined by immunohistochemical staining with an antibody against the vesicular monoamine transporter. There was a positive relationship between the density of [³H]1-methyl-4-phenylpyridinium label and the density of vesicular monoamine transporter immunoreactivity: the highest densities of both were found in the locus coeruleus and lowest densities in the midbrain dopaminergic neurons. In addition, [³H]1-methyl-4-phenylpyridinium labelling was detected in the bed nucleus of the stria terminalis and paraventricular nucleus of the thalamus, which also contained vesicular monoamine transporter immunoreactive nerve terminals.

The present data indicate that low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine cause a significant accumulation of 1-methyl-4-phenylpyridinium within monoaminergic somata in parallel with theamount of vesicular monoamine transporter in the neuron. Since nuclei with intense labelling are not damaged by doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine that are toxic to midbrain dopaminergic neurons, these data are consistent with the hypothesis that sequestration of 1-methyl-4-phenylpyridinium within monoaminergic synaptic vesicles can protect the neurons from degeneration caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.