Reduced MPTP neurotoxicity in striatum of the mutant mouse tottering.
The effects of MPTP treatment (4 x 10 mg/kg, 2-h intervals) on in vivo striatal binding of (+)-alpha-[3H]dihydrotetrabenazine ((+)-[3H]DTBZ) to the vesicular monoamine transporter type 2 (VMAT2) were examined in wild type (+,+) and tottering (tg/tg) mice of the C57BL/6J strain. The tottering mutant has been previously characterized as having hyperinnervation of noradrenergic terminals in the brain, with increased concentrations of norepinephrine and increased numbers of VMAT2 binding sites. In wild-type mice, MPTP caused a significant decrease in specific striatal (+)-[3H]DTBZ binding in both males (-71%) and females (-57%), consistent with dopaminergic terminal losses. In the tottering mice, the neurotoxic effects of MPTP were diminished, with smaller losses of (+)-[3H]DTBZ binding observed both in males (-45%) and females (-26%). These results are consistent with the hypothesis that vesicular storage (as a result of hyperinnervation) offers neuroprotection toward MPTP toxicity, although the confounding effects of increases in norepinephrine concentrations or changes in calcium ion channel function (both also characteristics of the tottering mutant) cannot be ruled out. The tottering mutant does, however, offer another animal model to examine the biochemical features responsible for MPTP toxicity.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109, USA. mkilbour@umich.edu
M R
MR
Kilbourn
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P
Sherman
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LC
Abbott
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D005260:Female; D020267:MPTP Poisoning; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D017072:Neostriatum / Q000473:pathology*; D009479:Neuropeptides; D009498:Neurotoxins / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000096:biosynthesis / Q000235:genetics; D017729:Presynaptic Terminals / Q000187:drug effects; D013045:Species Specificity; D014018:Tissue Distribution; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D009498:Neurotoxins; D018377:Neurotransmitter Agents; C493453:Slc18a2 protein, mouse; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D004298:Dopamine