FUNCTIONAL PLASTICITY OF THE DOPAMINE D1 RECEPTOR

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Considerable research over the past 30 years has provided strong evidence that dopamine (DA) plays a pivotal role in the expression of psychotic symptoms in schizophrenia. Similarly, DA appears to be involved in the pathophysiology of such developmental disorders as Tourette and Lesch- Nyhan Syndromes, as well as attention deficit disorder with hyperactivity. The physiological actions of DA are mediated by its interaction with D1 and D2 receptors (although D3, D4 and D5 receptors have putatively been identified with molecular biology methodology). Because D1 receptors mediate behavior on their own, as well as affecting the expression of D2 receptor-mediated behaviors, alterations of D1 receptor expression and activity may play important roles in the pathophysiology of disorders of DA neurotransmission such as schizophrenia and Tourette Syndrome. One long-term objective of this research program is to better understand D1 receptor function and plasticity following disruptions of normal dopaminergic activity during development. Results of both molecular biology and behavioral studies suggest that more than one D1 receptor subtype exists. Currently, the tools are not available to prove biochemically that there are two separate D1 subtypes, as selective drugs for these putative subtypes do not exist. Preliminary results suggest that there may be two D1 receptor systems which are differentially affected by depleting DA at different times during development. Thus, there may be two D1 receptor systems which develop independently and could possibly interact differentially with other receptor systems. Various pharmacological interventions will be utilized to alter the interaction between DA and its receptors during development. The organization and number of the various components of the DA system will be analyzed with quantitative receptor autoradiography and immunocytochemistry. A classical behavioral pharmacology approach will be used to study the functional plasticity of the D1 receptor(s) and how they interact with D2 receptors, as well as serotonin receptors, within the central nervous system. By using combinations of selective agonists and antagonists for DA and serotonin receptors, behavioral methods will be used to test for the presence of more than one D1 receptor subtype and determine their roles in the regulation of DA function. For example, there is evidence to suggest that D1 receptors modulate D2 receptor activity through both facilitatory and inhibitory interactions. These two types of interactions, which modulate distinct DA-mediated behaviors, may be regulated through two distinct subtypes of D1 receptors. Complementary binding studies will be carried out with quantitative receptor autoradiography, which allows for both quantification and discrete localization of the receptors of interest. A clearer understanding of which subtypes mediate particular psychomotor effects would promote development of more specific drugs and thus improve treatment of disorders involving abnormal DA neurotransmission.