MPTP INDUCED MODEL OF PARKINSON'S DISEASE

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Parkinson's disease is an idiopathic degenerative disorder affecting one in 1000 of the general population. This disorder affects the dopaminergic nigrostriatal system, as well as other monoaminergic systems, but does not become apparent clinically until the degenerative process is quite advanced. Although various approaches in search of an animal model of Parkinson's disease have been undertaken, none has proven to be a close parallel to human Parkinson's disease. Recently, human administration of MPTP, a potent neurotoxin, inadvertently injected as an illicit synthetic heroin produced Parkinsonian symptoms and nigrostriatal degeneration in humans. Injection of MPTP in non-human primates and rodents results in some motor disorder characteristic of Parkinsonism, and results in nigrostriatal degeneration. Thus MPTP may provide a model for some aspects of Parkinson's disease. These proposed studies will examine the effects of MPTP on the nigrostriatal and non-nigrostriatal monoaminergic systems in C57BL/6 mice at different ages. We will test the hypothesis that MPTP alters the meso-limbic dopaminergic and the locus coeruleus noradrenergic system, in addition to the nigrostriatal dopaminergic system. Based on our preliminary studies, we will further test the hypothesis that MPTP effects in aging mice, in which degeneration of the monoaminergic systems, has already begun as an age-related phenomenon, will be more severe than in young adult mice. We will treat mice at 3, 12, and 24 months of age with MPTP, and will examine the monoaminergic systems with fluorescence histochemistry for localization of cells and fibers, with micropunch neurochemistry for levels of monoamines and their metabolites, and with immunocytochemistry for tyrosine hydroxylase, dopamine-B-hydroxylase, 5-HT for morphometric analysis and cell counts in the substantia nigra, the ventral tegmental area, locus coeruleus, and raphe nuclei. Finally, we will pretreat mice with monoamine oxidase inhibitor, deprenil, prior to MPTP treatment to see if damage to the nigrostriatal dopaminergic and other monominergic systems can be prevented by pretreatment with MAO inhibitor. With this approach, we will establish the extent to which MPTP administration in young and aging mice can be used as a model for anatomical and neurochemical characteristics of Parkinson's disease.