Parkinson's disease is a neurodegenerative disorder in which the primary abnormality is the loss of the dopaminergic projection from the substantia nigra to the striatum. In addition, drugs affecting dopaminergic transmission are widely used in the treatment of Parkinson's disease and other conditions. The effects of dopamine have been shown to be mediated by two separate subtypes of the dopamine receptor, termed D-1 and D-2. Studies with selective agonists and antagonists have demonstrated that the D-1 and D-2 receptor produce differing pharmacologic and functional effects. The goal of this project is to determine the anatomic basis for these effects. This series of experiments will examine the cellular localization of the D-1 and D-2 receptor to specific neuronal populations in the striatum. We will use a newly developed technique for producing anatomically selective lesions within the brain. The cytotoxic lectin, volkensin, is taken up by nerve terminals and retrogradely transported, resulting in the death of those neurons projecting to the site of injection. The use of this technique in conjunction with quantitative film autoradiography and immunocytochemistry will address the question of the anatomic selectivity of receptor expression as a mechanism underlying specific neuropharmacologic effects. This application of the volkensin lesion will further characterize the methodology for wider use in new experimental investigations within the central nervous system. Better understanding of the anatomic substrate of dopamine action will have direct clinical applications in the use of selective agonists to treat Parkinson's disease, the use of selective antagonists to treat psychosis, and in the prevention of the side effects associated with these agents.
