The neurodegenerative diseases affecting the basal ganglia produce deficits in motor control, frequently in association with abnormalities of cognitive function. Parkinson's disease is one of the best understood of these conditions from a neuropharmacologic standpoint; the primary abnormality consists of loss of dopaminergic neurons in the substantia nigra. Improved understanding of the mechanisms of action of dopamine in the striatum through its two primary receptors, D1 and D2, has implications not only for the therapy of basal ganglia disease but also for the understanding of the actions of dopamine in other regions. We propose to investigate the hypothesis that the cellular localization of the D1 and D2 receptors to specific populations of striatal neurons is largely responsible for the specificity of effects produced by selective agonists and antagonists. We will use a newly developed technique for producing lesions with retrogradely transported toxins to explore not only receptor localization, but also changes in regulation of neurotransmitter and receptor expression in surviving neurons which are relevant to the study of neurodegenerative diseases in general.
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