The goal of the proposed project is to determine if the relative distributions of the plasma membrane dopamine transporter (DAT) and the synaptic vesicular monoamine transporter (VMAT2) underlie MPTP-induced parkinsonism and idiopathic Parkinson's disease.
The Specific Aims are I. Determine the relative distribution of DAT and VMAT2 protein in mouse brain, and the effect of age on the relative distribution, II. Determine the effects of low, high, and repeated doses of MPTP on the relative distribution of DAT and VMAT2 protein in mouse brain, III. Determine the relative distribution of DAT and VMAT2 protein in monkeys subjected to unilateral MPTP administration. The relative distribution of the DAT and VMAT2 protein will be determined using specific antibodies to the respective proteins and immunocytochemical and quantitative immunoblotting techniques in the nigrostriatal dopamine system. DAT and VMAT2 protein distribution will be determined in mice of various age, mice subjected to low, high, and repeated MPTP exposure, and in hemiparkisonian monkeys. Completion of the Specific Aims will provide a detailed map of DAT and VMAT2 protein in mouse and monkey brain. Further, it will be possible to determine the effects of prior exposure to MPTP on subsequent MPTP-induced damage and the potential role of DAT and VMAT in the altered susceptibility. This information can be used in the development of new pharmacological strategies aimed at attenuating damage to dopaminergic neurons in patients in the early stages of Parkinson's disease. In addition, these experiments will provide useful data concerning the localization of transporters involved in cocaine and amphetamine pharmacology.
