ALPHA2-ADRENERGIC RECEPTOR SUBTYPES IN THE CNS

CNS 中的 ALPHA2 肾上腺素受体亚型

• 批准号: 3213883
• 负责人: KEVIN R. LYNCH
• 金额: $ 17.04万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213883
• 关键词: alpha adrenergic receptor; anesthetics; animal age group; antihypertensive agents; autoradiography; binding proteins; brain mapping; catecholamines; chimeric proteins; chlorpromazine; denervation; drug design /synthesis /production; drug withdrawal; electrophysiology; enzyme linked immunosorbent assay; guanine nucleotides; haloperidol; hippocampus; immunocytochemistry; laboratory rat; locus coeruleus; medulla oblongata; molecular cloning; neuroanatomy; neuropharmacology; polymerase chain reaction; serotonin; spinal cord mapping; thioridazine; tissue /cell culture; transfection

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?

α 2-肾上腺素能受体介导大部分已知的 儿茶酚胺对中枢和外周神经元的抑制作用。 α 2-肾上腺素能受体激动剂的抑制特性使得 这些药物中的几种可用作抗高血压药， 挥发性麻醉剂和钝化自主神经和情感症状 阿片类药物戒断 经典的药理学方法（配体结合， 发射机溢出）最近促成了部分 α 2-肾上腺素能受体的几种亚型的表征。 然而，这些受体的特定药理学特征仍然存在， 它们在神经组织中的解剖学作用需要 详细探索。 最近的分子克隆三个 α 2-肾上腺素能受体DNA使新的和强大的 了解这些重要的生物学作用的方法 proteins. 我们建议使用这些新的试剂来鉴定精确的 药理学特征和神经解剖学位置 α 2肾上腺素能受体亚型。 每一种亚型都将被表达 在相同的细胞环境和药理学 根据各种潜在的活性化合物来定义。 亚型特异性抗血清，针对每种重组片段产生 受体，将产生和严格的测试。 这些抗血清将 通过化学方法检测大脑受体亚型， 通过光学和电子显微镜染色脑切片。 相关 免疫组织化学绘图的一部分将包括电生理学 结合亚型特异性化合物和杂交的分析 组织化学 虽然整个中枢神经系统和将被检查，我们将 集中精力在几个肾上腺素活性高的区域 包括蓝斑，延髓腹外侧头端， 海马和脊髓的中间外侧细胞柱。 除了定义药理学和解剖学 α 2-肾上腺素能受体的位置，我们的结果可能有助于 合理设计用作抗高血压药的药物， 与吸入性麻醉剂联合使用， 阿片类药物戒断症状 最后，我们的研究结果可能有助于解决 受体生物学中的一个重要问题，即为什么有多个， 表面上密切相关的受体亚型的每一个阳离子 胺？