COMPARISON OF KEY STEPS IN 1-METHYL-4-PHENYL-1,2,4,6-TETRAHYDROPYRIDINE (MPTP) NEUROTOXICITY IN RODENTS

Three steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neu rotoxicity were compared with the neurodegenerative effects of the tox in in mice and rats. Firstly we compared the neurotoxicity of MPTP, me diated by monoamine oxidase (MAO)-B, to that of hyl-4-(2'-methylphenyl )-1,2,3,6-tetrahydropyridine (2'-CH3-MPTP), an analogue oxidized by MA O-A and MAO-B. Both toxins caused degeneration of dopamine terminals i n mice but not in rats. In NMRI mice noradrenaline terminals were also affected by both toxins. Pretreatment with deprenyl to prevent MAO-B- mediated oxidation in the capillary endothelium enhanced dopamine toxi city to 2'-CH3-MPTP in nucleus accumbens but no potentiation was seen in striatum and the olfactory tubercle. Secondly, synaptosomal uptake of the 1-methyl-4-phenylpyridinium ion (MPP+) was studied. Uptake in r ats was not significantly different from that in the two mice strains. Thirdly, no significant differences were found in MPP+-induced lactat e production in striatal slices or synaptosomes. We conclude that the lack of effect of MPTP in rats is not due to mechanisms specific for M PTP but probably to the ability of rat catecholamine neurons to cope w ith, and survive, impaired energy metabolism.