CNS GABA PHARMACOLOGY & CONTROL OF AUTONOMIC FUNCTION

CNS GABA 药理学

• 批准号: 3399979
• 负责人: JOSEPH A DIMICCO
• 金额: $ 11.64万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3399979
• 关键词: aminoacid biosynthesis; aminoacid inhibitor; autonomic nervous system; benzodiazepines; cardiovascular disorder; cardiovascular function; central nervous system; centrally acting drug; emotions; gamma aminobutyrate; hypertension; hypothalamus; neural information processing; neurochemistry; neuroendocrine system; neuropharmacology; parasympathetic nervous system; psychological stressor; reflex; stress; sympathetic nervous system; vasopressins

The central nervous system is thought to play an important role in regulating cardiovascular function. Increasingly, this role is appreciated in causing or exacerbating disorders of the cardiovascular system in man. In spite of this, relatively little is known about the pathways in the brain that regulate functions ultimately impacting on regulation of blood pressure and heart rate and rhythm. this is particularly true with regard to forebrain mechanisms that integrate and generate the responses to environmental or emotional stress which have been implicated in such catastrophic clinical events as sudden death, myocardial infarction and hypertension. The long range goal of this research is to elucidate the central nervous system pathways and mechanisms which influence cardiovascular control though the autonomic nervous system or through neuroendocrine factors. The approach taken is to study the effects of drugs which interact with the inhibitory neurotransmitter gamma aminobutyric acid (GABA), commonly thought to be the most prevalent neurotransmitter in the mammalian central nervous system. By examining the changes resulting from pharmacologically modifying GABA function in discrete regions of the brain in anesthetized and conscious rats, different roles for this substance in controlling sympathetic and parasympathetic activity to the heart and vasculature or in regulating the release of neuroendocrine factors with cardiovascular effects can be inferred. Specifically, this research proposes to: (1) investigate and characterize the pattern of cardiovascular and other associated changes resulting from altering GABA function in the posterior hypothalamus in anesthetized and conscious rats, and to determine the role that this region and local GABAergic inhibition may play in the physiological changes associated with stress and emotion; (2) determine the site in the forebrain where GABAergic drugs act to influence the release of vasopressin, a hypothalamic neurohormone with important cardiovascular effects;and (3) study the interaction of benzodiazepines, a widely used class of drugs now thought to exert their characteristic effects primarily by interacting with endogenous GABA, and other agents acting at benzodiazepine receptors with the mechanisms elucidated in (1) and (2) above. The results of these studies may enhance our understanding of the neural basis for certain cardiovascular disorders and suggest specific strategies for drug development and therapy aimed at their treatment or prevention.

中枢神经系统被认为在以下方面发挥着重要作用： 调节心血管功能。 这个角色越来越多地 引起或加剧疾病的赞赏 人的心血管系统。 尽管如此，相对而言， 了解大脑中调节功能的通路 最终影响血压和心脏的调节 速率和节奏。 对于前脑来说尤其如此 整合并生成响应的机制 与环境或情绪压力有关的 猝死、心肌梗塞等灾难性临床事件 梗塞和高血压。 本研究的长期目标 目的是阐明中枢神经系统通路 影响心血管控制的机制 自主神经系统或通过神经内分泌因素。 采取的方法是研究药物相互作用的影响 与抑制性神经递质 γ 氨基丁酸 (GABA)，通常被认为是最普遍的 哺乳动物中枢神经系统中的神经递质。 经过 检查药理学引起的变化 改变大脑离散区域的 GABA 功能 麻醉和清醒的老鼠，这种物质的不同作用 控制交感神经和副交感神经的活动 心脏和脉管系统或调节释放 神经内分泌因素对心血管的影响可 推断。 具体来说，本研究建议：（1）调查 并描述心血管和其他疾病的模式 改变 GABA 功能导致的相关变化 麻醉和清醒大鼠的下丘脑后部，并 确定该区域和局部 GABA 能抑制的作用 可能会影响与压力相关的生理变化 情感; (2) 确定前脑中GABA能的位点 药物的作用是影响血管加压素（下丘脑的一种物质）的释放 具有重要心血管作用的神经激素；以及（3）研究 苯二氮卓类药物（一类广泛使用的药物）的相互作用 现在认为主要通过 与内源性 GABA 和其他作用于 苯二氮卓受体，其机制在 (1) 中阐明 和上述（2）。 这些研究的结果可能会增强我们的 了解某些心血管疾病的神经基础 疾病并提出药物开发的具体策略和 治疗旨在治疗或预防。