Studies on species sensitivity to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Part 1: Systemic administration.
Several parameters necessary for the expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity to dopaminergic neurons were examined in both mice and rats in order to determine if differences in these processes might underlie the marked differences in the sensitivity of the two species to the neurotoxic effects of MPTP. Monoamine oxidase-B activity was greater in brain tissues from rats than from mice. The kinetics of 1-methyl-4-phenylpyridinium (MPP+) uptake into neostriatal synaptosomal preparations from the two species were similar. Brain and neostriatal levels of MPP+ were 2-fold higher in rats after the administration of MPTP at 60 mg/kg and were 10 to 20 times higher in rats than in mice after MPTP treatment which produced similar decrements in the content of neostriatal dopamine. MPP+ concentrations in the extracellular fluid of the neostriatum of the two species were similar after the administration of the same dose of MPTP (40 mg/kg). However, this dose induced a 40-fold increase in neostriatal dopamine efflux in mice, whereas in rats only a 3-fold increase was observed. In addition, pretreatment of rats with guanethidine, a ganglionic blocking agent, permitted the use of high doses of MPTP which resulted in substantial damage to the striatal dopaminergic nerve terminals. It is concluded that nigrostriatal dopaminergic neurons in the rat require exposure to a much higher concentration of MPP+ than do those in mice for the induction of toxicity.
Giovanni
A
A
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway.
Sieber
B A
BA
Heikkila
R E
RE
Sonsalla
P K
PK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000493:pharmacokinetics; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006145:Guanethidine / Q000494:pharmacology; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D017551:Microdialysis; D008995:Monoamine Oxidase / Q000378:metabolism; D017072:Neostriatum / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013574:Synaptosomes / Q000378:metabolism
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