The objective of the proposed project is the characterization of the properties of the different types of serotonin (5-hydroxytryptamine, 5-HT) receptors in the mammalian central nervous system (CNS). One part of this involves the use of in vitro binding assays utilizing ligands such as [H-3]5-HT, [H-3]PAT, and [H-3] ketsanserin, which are thought to label specific populations of serotonin receptors. A major emphasis of this work will be the pharmacological characterization of these receptors to determine the structural requirements of compounds for discrimination between different types of 5-HT receptors. In conjunction with the ligand-binding assays a program for the synthesis of new compounds will be carried out. Thus, information form the binding assays will be used in the design of new compounds for testing at 5-HT receptors. Another part of the project will be the characterization of functional 5-HT receptors, both in vitro and in vivo. This will include examination of 5-HT receptors that mediate contraction of the cerebral vasculature and 5-HT autoreceptors that regulate the release of 5-HT, as well as examination of central 5-HT receptors involved in the control of respiration, blood pressure, body temperature, and release of certain pituitary hormones such as prolactin and thyrotropin. The study of functional receptors will provide information as to whether the compounds are agonists or antagonists of 5-HT and whether the properties of the functional receptors correlate with those of the putative receptors measured by ligand-binding. As with the ligand-binding studies, a major emphasis of this portion of the project will be the attempt to determine the structural requirements of compounds for discrimination between different types of 5-HT receptors. Once these groups of receptors are classified and characterized, it is hoped that more specific drugs can be designed that will facilitate the study of the roles and actions of 5-HT in the CNS. It is hoped that information from such studies can be used for the design of new, more effective therapeutic agents for the treatment of behavioral or mental disorders that are thought to be linked to abnormal serotonergic function in the central nervous system.
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