Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 2: Central administration of 1-methyl-4-phenylpyridinium.
There are marked species differences in susceptibility to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice are sensitive, whereas rats are relatively insensitive to MPTP. In these two species, the effects of peripherally administered MPTP or intrastriatally infused 1-methyl-4-phenylpyridinium (MPP+) were examined to identify potential underlying mechanisms responsible for their difference in susceptibility to MPTP. In vivo intrastriatal microdialysis and an MPP+ 2-day test/challenge paradigm were used to monitor dopamine efflux as an indicator of the neurotoxic effects of MPTP or MPP+. By using this method, the EC50 for neurotoxicity by an intrastriatal infusion of MPP+ in mice was 0.4 mM, whereas it was 10-fold higher in rats (4.3 mM). In addition, by using the traditional postmortem examination, neostriatal dopamine was depleted markedly in mice (> or = 80%), but only depleted marginally in rats in which MPP+ was infused into the neostriatum. These data indicate that rats are relatively insensitive to MPTP as compared to mice, because they are less sensitive to MPP+ whether it is formed in vivo from MPTP administered systemically or administered directly into neostriata. Thus, there appears to be a fundamental difference in the susceptibility of the nigrostriatal systems in these two species to the neurotoxic consequences of MPP+ exposure.
Giovanni
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A
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway.
Sonsalla
P K
PK
Heikkila
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RE
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics; D015655:1-Methyl-4-phenylpyridinium / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006145:Guanethidine / Q000494:pharmacology; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D015102:3,4-Dihydroxyphenylacetic Acid; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D003042:Cocaine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D006145:Guanethidine