In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): Rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium

Citation
Rgw. Staal et al., In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): Rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium, J PHARM EXP, 293(2), 2000, pp. 329-335
Citations number
36
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
293
Issue
2
Year of publication
2000
Pages
329 - 335
Database
ISI
SICI code
0022-3565(200005)293:2<329:IVSOSV>2.0.ZU;2-W
Abstract
Significant differences exist in the sensitivity of mice and rats to the ne urotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that can not be explained by differences in exposure to or uptake of 1-methyl-4-phen ylpyridinium (MPP+) into dopamine (DA) neurons. MPP+ is also a substrate fo r the brain vesicular monoamine transporter (VMAT2), and sequestration into synaptic vesicles may be one mechanism of protection against MPP+ toxicity . A greater sequestration of MPP+ into vesicles of DA neurons in rats versu s mice could explain the lower vulnerability of DA neurons in the rat to MP P+ toxicity. To test this hypothesis, the kinetics of uptake for [H-3]MPPand [H-3]DA as well as [H-3]dihydrotetrabenazine binding to VMAT2 were comp ared in vesicles isolated from the striata of rats and mice. The K-m value of [H-3]MPP+ transport was similar in the two species. In contrast, the max imal transport rate (V-max) was 2-fold greater in vesicles from rats than i n those from mice. Likewise, the K-m value for [H-3]DA transport was simila r in both preparations, but the V-max value was 2-fold greater in rat than in mouse vesicles. The B-max value for [H-3]dihydrotetrabenazine binding wa s also 2-fold greater in striatal vesicles from rats than in those from mic e. Electron micrographs demonstrated that vesicles isolated from rats and m ice were approximately the same size. Based on these observations, we propo se that striatal vesicles from rats have more VMAT2 than vesicles from mice and that this species difference in VMAT2 density may help explain the red uced vulnerability of rat DA neurons to MPP+ neurotoxicity.