Dopamine dysfunction plays a key role in a number of diseases of the basal ganglia including Parkinson's disease, Huntington's disease, and Tourette Syndrome. Pharmacological and physiological studies suggest that the normal function of dopamine in the striatum depends upon interactions between the two major classes of dopamine receptors, D1 and D2. However, little is known about the neuronal substrate for the functional interaction of dopamine receptors in the normal striatum, the upregulation of dopamine receptor activity at the cortical and pallidal level to the regulation of basal ganglia output. Using well-characterized peptide specific antibodies for immunohistochemistry and oligonucleotide probes for in situ hybridization, a series of light and electron microscopic studies is planned to investigate the neuronal circuitry of the basal ganglia in which D1 and D2 receptors mediate the actions of dopamine.
The specific aims are: 1) To examine the extent of colocalization and subcellular distribution of D1 and D2 receptor proteins in identified striatal output neurons and interneurons and to compare these findings to the distribution of mRNA for D1 and D2; 2) To determine the basis for dopamine receptor upregulation by studying the cellular and subcellular changes in distribution of D1 and D2 receptors in rats receiving 6-OHDA lesions of the substantia nigra or chronic drug treatment with dopamine receptor antagonists; 3) To explore the role of the corticostriatal pathway in dopamine regulation by a: determining whether cortical neurons which project to the striatum contain dopamine receptors and b: determining whether NMDA receptors are localized to dopaminergic nigrostriatal axons in the striatum; and 4) To study the relationships in the rodent pallidal complex between dopamine inputs, D1 and D2 receptors, and striatopallidal axons. Knowledge obtained from these studies will enhance our understanding of the neuronal circuits in which dopamine regulates motor behavior in the basal ganglia and help in the development of pharmacological therapies to treat movement disorders.
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