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

A. Giovanni, P. K. Sonsalla, R. E. Heikkila

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Abstract

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 (≥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.

Original languageEnglish (US)
Pages (from-to)1008-1014
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume270
Issue number3
StatePublished - 1994

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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