This study will examine the effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on monoaminergic systems in addition to the nigrostriatal dopaminergic system in 3 and 21 month old C57BL/6 male mice. The studies proposed in this project will provide sufficient pilot data to test the hypothesis that (a) MPTP treatment in adult C57BL/6 mice alters other monoaminergic systems in addition to the nigrostriatal dopaminergic system, and (b) 21 month old C57BL/6 mice, who already demonstrate deterioration of nigrostriatal dopaminergic and locus coeruleus noradrenergic system as part of the natural aging process, are more sensitive to MPTP treatment than 3 months old mice. To test these hypotheses, we will pursue the following specific aims: (1) mice at 3 and 21 months of age will be tested for a dose-response relationship between MPTP treatment and altered monoamine systems, including both nigrostriatal and non-nigrostriatal dopaminergic, noradrenergic and serotonergic systems using fluorescence histochemistry for catecholamine localization and quantitation of cell body numbers and nerve terminal densities, tyrosine hydroxylase immunocytochemistry with computerized cytomorphometry for call counts of DA neurons in substantia nigra and the ventral tegmental area, and dopamine-B-hydroxylase immunocytochemistry for NE neurons in locus coeruleus as well as the density of nerve terminals in their major projection fields, and micropunch neurochemistry with high performance liquid chromatography with electrochemical detection (LCEC), (2) following the same treatment protocol and experimental design, treated and control mice will be allowed to survive for 2 weeks or 2 months after the last injection to examine the short and long-term effects of MPTP treatment on the parameters designed above. These studies should yield sufficient pilot data to determine the usefulness of MPTP neurotoxicity as model for Parkinson's disease not only for anatomical and neurochemical damage to the nigrostriatal system, but also for damage to other monoamine systems known to be affected in humans with Parkinson's disease and in Psychiatric disorders.
| Gupta, M; Stoler, M H; Fossom, L H et al. (1990) Tyrosine hydroxylase mRNA in the dopaminergic neurons of young adult and aged mice by in situ hybridization. Neurosci Lett 119:49-52 |
| Gupta, M; England, M A; Notter, M F (1987) Effects of antimitotic drugs on the morphological features of PC12 cells in culture--a light and EM study. Brain Res Bull 18:555-61 |
