This study will examine the effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on the nigrostriatal dopaminergic system, and other non-nigrostriatal monoaminergic systems in adult and aging C57BL/6 mice. We will test the hypothesis that: (1) MPTP treatment in adult C57BL/6 mice alters other monoaminergic systems in addition to the nigrostriatal dopamine system; (2) aging C57BL/6 mice, demonstrating depletion of the nigrostriatal dopamine system as part of the natural aging process, are more sensitive to MPTP treatment than young adults; (3) MPTP treatment results in cell death in substantia nigra (SN), and remaining neurons undergo compensatory synaptic reorganization, (4) treatment of adult and aging mice with MAO-B inhibitor, Deprenil, prior to MPTP treatment will protect against resultant cell death and subsequent reorganization; and (5) MPTP induced alterations in the nigrostriatal dopaminergic system result in post-synaptic changes in striatal peptides. To test these hypotheses, we will pursue the following specific aims: (i) mice at 3, 12, and 24 months of age will be tested for a dose-response relationship between MPTP treatment and altered monoamine systems, including both nigrostriatal and non-nigrostriatal systems, using fluorescence histochemistry for catecholamine localization, tyrosine hydroxylase immunocytochemistry with computerized cytomorphometry for dopamine cell counts, Nissl staining for assessment of neurons in SN with computerized cytomorphometry, and micropunch neurochemistry with high performance liquid chromatography with electrochemical detection; (ii) mice at 3, 12, and 24 months of age will be treated with MPTP and allowed to survive for 1, 3, 10, and 30 weeks, followed by electronmicroscopic morphometric analysis of remaining nigral neurons and synaptic inputs into their cell bodies and dendrites; (iii) mice at 3, 12, and 24 months of age will be pretreated with deprenil prior to MPTP to ascertain the protective capability of MAO-B inhibitors; and (iv) following the same treatment and survival schedule as Specific Aim 2, the chemical levels and the distribution and density of immunostaining of met-enkephalin, somatostatin, dynorphin, and substance P will be evaluated in the striatum by RIAs and computerized image analysis (Magiscan), respectively. This approach should yield a better understanding of MPTP neurotoxicity as a possible adult model or aging model for neuroanatomical and neurochemical changes seen in Parkinson's disease, and a better understanding of how SN neurons respond to toxic insult and how striatal peptides respond secondarily to altered SN dopamine activity.
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