ETHANOL-INDUCED CHANGES IN B-ENDORPHIN AND CRF BINDING TO PERIPHERAL TISSUE

乙醇引起的 B-内啡肽和 CRF 与外周组织结合的变化

• 批准号: 4687731
• 负责人: R ESKAY
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4687731
• 关键词: adenylate cyclase; adrenocorticotropic hormone; alcoholism /alcohol abuse; chemical binding; chromaffin cells; corticotropin releasing factor; cyclic AMP; ethanol; hormone regulation /control mechanism; liver cells; membrane activity; neurochemistry; pituitary adrenal axis; radiotracer; stress; tissue /cell culture; toxicology; vasopressins

Although ethanol is commonly regarded as an anxiolytic, its administration mimics many actions of stress that involve activation of the hypothalamic-pituitary-adrenal axis (HPAA). An understanding of the effect of ethanol on this axis requires an appreciation of the central and peripheral regulatory factors and their interactions, which constitute the HPAA. Intimately involved in the homeostasis of the HPAA are several neuropeptides of brain origin (vasopressin and corticotropin-releasing factor [CRF]) and pituitary origin (beta-endorphin [BE] and adrenocorticotropin). The long-term goal of these studies is to understand the effect of ethanol at each level of the HPAA, with special emphasis on neuropeptide-dependent events. Before evaluating ethanol-induced perturbations of CRF and BE, it was necessary to validate the existence of specific BE and CRF binding sites in peripheral tissues, and to determine if occupancy of these receptors altered any of the known second-messenger systems. We have (1) identified, using 125-I-rCRF, specific binding sites for CRF in various rat peripheral tissues and bovine chromaffin cells in culture and (2) established that occupancy of the CRF binding sites, at least in rat adrenal membranes and bovine chromaffin cells, activates the adenylate cyclase/cAMP system. Furthermore, we have (1) identified, using 125-I-human BE, specific binding sites for BE in various rat peripheral tissues and (2) established that occupancy of the BE binding sites, at least in rat hepatic membranes, activates the adenylate cyclase/cAMP system. Exposure of rats to ethanol vapor for 14 days lowered immunoreactive plasma BE levels and reduced CRF and BE binding to a variety of peripheral tissues. In addition, chronic exposure of rats to ethanol vapors lowered pituitary CRF binding, basal and CRF-stimulated adenylate cyclase activity, and pro-opiomelanocortin messenger RNA levels.

虽然乙醇通常被认为是一种抗焦虑药， 模仿了许多涉及激活 下丘脑-垂体-肾上腺轴（HPAA）。 对影响的理解 乙醇在这条轴上的分布需要对中心和 外周调节因子及其相互作用，构成了 HPAA。 与HPAA的内稳态密切相关的是几种 脑源性神经肽（血管加压素和促肾上腺皮质激素释放肽 因子[CRF]）和垂体来源（β-内啡肽[BE]和 促肾上腺皮质激素）。 这些研究的长期目标是了解 乙醇在HPAA各水平的影响，特别强调 神经肽依赖性事件。 在评价乙醇诱导的 由于CRF和BE的扰动，有必要验证 外周组织中特异性BE和CRF结合位点，并确定 如果这些受体的占据改变了任何已知的第二信使， 系统. 我们已经（1）确定，使用125-I-rCRF，特异性结合位点 CRF在各种大鼠外周组织和牛嗜铬细胞中的表达， 培养和（2）建立CRF结合位点的占用率， 至少在大鼠肾上腺膜和牛嗜铬细胞中， 腺苷酸环化酶/cAMP系统。 此外，我们（1）确定，使用 125-I-人BE，各种大鼠外周血中BE的特异性结合位点 组织和（2）建立了BE结合位点的占有率，在 至少在大鼠肝膜中，激活腺苷酸环化酶/cAMP 系统 大鼠暴露于乙醇蒸汽14天降低 免疫反应性血浆BE水平和减少CRF和BE结合到各种 周围组织。 此外，大鼠长期接触乙醇 蒸汽降低垂体CRF结合，基础和CRF刺激的腺苷酸 环化酶活性和前阿黑皮素信使RNA水平。