THE NEUROTOXIN 1-METHYL-4-PHENYLPYRIDINIUM IS SEQUESTERED WITHIN NEURONS THAT CONTAIN THE VESICULAR MONOAMINE TRANSPORTER

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine produces a parkinsonian syndrome in man and experimental animals. The toxic meta bolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1-methyl-4-phe nylpyridinium, exhibits high-affinity uptake by plasma membrane monoam ine transporters and also by the vesicular monoamine transporter. Usin g autoradiographic and immunohistochemical methods in mice, we demonst rate the accumulation of [H-3]1-methyl-4-phenylpyridinium within neuro ns that contain the vesicular monoamine transporter, following systemi c administration of [H-3]1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Within 1-24 h following the intraperitoneal administration of 10 mu g /kg of [H-3]1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, [H-3]1-methy l-4-phenylpyridine labelling was found within such regions as the locu s coeruleus, dorsal, medial, and pallidal raphe nuclei, substantia nig ra 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 bet ween the density of [H-3]1-methyl-4-phenylpyridinium label and the den sity of vesicular monoamine transporter immunoreactivity: the highest densities of both were found in the locus coeruleus and lowest densiti es in the midbrain dopaminergic neurons. In addition, [H-3]1-methyl-4- phenylpyridinium labelling was detected in the bed nucleus of the stri a terminalis and paraventricular nucleus of the thalamus, which also c ontained vesicular monoamine transporter immunoreactive nerve terminal s, 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-p henylpyridinium within monoaminergic somata in parallel with the amoun t 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 call protect the neurons from degeneration caused by 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine. (C) 1998 IBRO. Published by Elsevier Science L td.