Treatment of animals with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-- tetrahydropyridine (MPTP) results in movement disorders and signs of injury to striatal dopamine nerve terminals that are similar to those observed in patients with Parkinson's Disease (PD). Patients with PD, like MPTP-treated animals, suffer regionally heterogeneous injury to striatal dopaminergic terminals. That is, the extent of damage is greater in dorsal striatum than ventrally, and the nucleus accumbens septi (NAc) dopamine inputs are largely spared. Preliminary data indicate that mice, rats, rabbits, and humans have a higher density of dopamine uptake sites (determined by [3H]DA uptake kinetics or [3H]mazindol binding to the associated recognition site) in dorsal striatum than ventrally, with particularly low levels observed in NAc. The present studies seek to determine whether regional striatal [3H]mazindol binding densities in young adult and mid-age mice are predictive of regional MPTP-induced injury to the dopamine systems of the striatum, as well as of extrastriatal structures. Further, an analysis will be undertaken of the distribution of [3H]mazindol binding sites in human striatal tissue obtained postmortem. These studies should (i) contribute to an understanding of the mechanism of MPTP neurotoxicity in animals, (ii) add to our knowledge of the physiological and pathophysiological significance of high-affinity dopamine uptake, and (iii) provide novel information regarding the hypothesis that the incorporation of environmental neurotoxins via the high-affinity DA uptake system contributes to the etiology of PD.
