Alpha2-Adrenergic receptors mediate a large portion of known inhibitory effects of catecholamines on central and peripheral neurons. The inhibitory properties of alpha2-adrenergic receptor agonists make several of these drugs useful as antihypertensives, in potentiating volatile anesthetics and in blunting the autonomic and affective symptoms of opiate withdrawal. Classic pharmacologic approaches (ligand binding, transmitter overflow) have recently contributed towards the partial characterization of several subtypes of alpha2-adrenergic receptors. However, the specific pharmacologic profile of these receptors remains imprecise and their anatomical Ioaction in neural tissue needs to be explored in detail. The recent molecular cloning of three alpha2-adrenergic receptor DNAs makes possible new and powerful approaches to understanding the specific biologic role of these important proteins. We propose to use these novel reagents to identify the precise pharmacologic profile and the neuroanatomical locations of alpha2-adrenergic receptor subtypes. Each subtype will be expressed individually in the same cellular environment and their pharmacologies defined in terms of a wide variety of potentially active compounds. Subtype-specific antisera, raised against recombinant fragments of each receptor, will be generated and rigorously tested. These antisera will be used to map brain receptor subtypes by examining immunohistochemically stained brain sections by both light and electron microscopy. Correlates of the immunohistochemical mapping will include electrophysiologic analyses in conjunction with subtype-specific compounds and hybridization histochemistry. Although the entire CNS and will be examined, we will concentrate our efforts on several areas with high adrenergic activity including the locus coeruleus, rostral ventral lateral medulla, hippocampus and intermediolateral cell column of the spinal cord. In addition to defining the pharmacology and anatomical location of the alpha2-adrenergic receptors, our results might aid in the rational design of pharmaceuticals to be used as antihypertensives, in conjunction with inhalational anesthetics and to alleviate the noxious symptoms of opiate withdrawal. Finally, our results might help address an important issue in receptor biology, i.e. why are there multiple, apparently closely related, receptor subtypes for each of the cationic amines?
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