Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons

Citation
Dc. German et al., Pharmacological inactivation of the vesicular monoamine transporter can enhance 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurodegeneration of midbrain dopaminergic neurons, but not locus coeruleus noradrenergic neurons, NEUROSCIENC, 101(4), 2000, pp. 1063-1069
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
NEUROSCIENCE
ISSN journal
0306-4522 → ACNP
Volume
101
Issue
4
Year of publication
2000
Pages
1063 - 1069
Database
ISI
SICI code
0306-4522(2000)101:4<1063:PIOTVM>2.0.ZU;2-B
Abstract
The vesicular monoamine transporter in the brain can sequester the neurotox in 1-methyl-4-phenylpyridinium into synaptic vesicles and protect catechola mine-containing neurons from degeneration. Mouse nigrostriatal dopaminergic neurons, and to a lesser extent locus coeruleus noradrenergic neurons, are vulnerable to toxicity produced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyr idine. The present study sought to determine whether pharmacological inacti vation of the vesicular monoamine transporter in the brain would enhance th e degeneration of substantia nigra dopaminergic neurons and locus coeruleus noradrenergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-trea ted animals. Mice were treated subacutely with 1-methyl-4-phenyl-1,2,3,6-te trahydropyridine alone, or in combination with vesicular monoamine transpor ter inhibitors (tetrabenazine or Ro4-1284), and 10-24 days later striatal d opamine and cortical norepinephrine levels were measured using chromatograp hic methods. In the same animals, substantia nigra and locus coeruleus cate cholaminergic neurons were counted using tyrosine hydroxylase immunohistoch emical staining with computer imaging techniques. Mice in which pharmacolog ical blockage of the vesicular monoamine transporter enhanced the effects o f 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in the depletion of striatal dopamine concentrations also exhibited enhanced degeneration of s ubstantia nigra dopaminergic neurons. In the same animals, however, vesicul ar monoamine transporter blockade did not enhance the effects of 1-methyl-4 -phenyl-1,2,3,6-tetrahydropyridine in the locus coeruleus noradrenergic sys tem. These data are consistent with the hypothesis that the vesicular monoamine transporter can protect catecholamine-containing neurons from 1-methyl-4-ph enylpyridinium-induced degeneration by sequestration of the toxin within br ain vesicular monoamine transporter-containing synaptic vesicles. Since the amount of vesicular monoamine transporter in locus coeruleus neurons is mo re than in substantia nigra neurons, and because 1-methyl-4-phenylpyridiniu m is sequestered within locus coeruleus neurons to a far greater extent tha n within substantia nigra neurons, it may be that a greater amount of vesic ular monoamine transporter inhibition is required for 1-methyl-4-phenylpyri dinium to be toxic to locus coeruleus neurons than to substantia nigra dopa minergic neurons. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rig hts reserved.