CHRONIC DRUG ACTIONS ON G PROTEIN COUPLED RECEPTOR MECHANISMS

G 蛋白偶联受体机制的慢性药物作用

• 批准号: 6332487
• 负责人: Steven R Childers
• 金额: $ 19.12万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6332487
• 关键词: G protein; autoradiography; biological signal transduction; cocaine; corpus striatum; dopamine receptor; drug abuse; drug administration rate /duration; drug screening /evaluation; forskolin; laboratory rat; membrane transport proteins; morphine; neuropharmacology; opioid receptor; pharmacokinetics; receptor coupling; receptor sensitivity; second messengers; serotonin receptor; tropanes

Many neurotransmitters in brain, as well as several drugs of abuse, act by binding to receptors belonging to the superfamily of G-protein-coupled receptors. These drugs include the opioids, which act directly at their own G-protein receptors, and cocaine, which increases extra-synaptic dopamine that binds to its own receptor. The goal of this project is to utilize animal models provided by the Center to examine how chronic treatment with opioids and psychostimulants affect coupling of different receptors to G-proteins in brain, and how these changes at the level of the receptor amd transducer then translate into downstream changes in opioid-mediated second messenger systems. In the first case, the coupling of receptor to G-proteins will be explored by [35/S]GTPgammaS autoradiography, which provides a neuroanatomical localization of the activation of G-protein receptors. Because this technique allows for a number of different receptors to be assayed simultaneously in brain sections from the same animals, this provides an ideal method to efficiently analyze brain tissue from Center-derived animals. This project will follow up on previous studies which showed that chronic morphine treatment produced selective attenuation of mu opioid-activated G-proteins in specific brainstem nuclei. These studies will determine the time course of the chronic morphine effect, and compare chronic treatment of rats with morphine to chronic treatment with other opioid agonists of different potencies and efficacies. The effects on non-contingent chronic administration morphine. To determine how these changes in receptor-G- protein coupling affect opioid second messenger systems, rats treated in the same way will be analyzed for opioid inhibition of forskolin- stimulated pro-enkephalin signal transduction systems in vivo. A second aim will examine the effect of chronic administration of cocaine and other psychostimulants on receptor-coupled G-proteins, with a particular focus on D2 dopamine receptors, 5-HT/1A receptors, and opioid receptors. To determine the effects of transporter selectivity and pharmacokinetics on modulation of receptor coupling to G-proteins, novel tropanes synthesized by the Center with well-defined specificities and durations of action will be administered chronically. This project will use information obtained from other Center projects in the planning of its studies, and provide information about receptor changes during chronic drug treatment that will be important for studies in other projects.

大脑中的许多神经递质，以及一些滥用的药物， 与属于G蛋白偶联超家族的受体结合 受体。这些药物包括阿片类药物，它们直接作用于它们的 自己的G蛋白受体，可卡因，增加突触外 与自身受体结合的多巴胺该项目的目标是 利用中心提供的动物模型， 阿片类药物和精神兴奋剂治疗影响不同的 大脑中G蛋白的受体，以及这些受体在大脑中的水平上如何变化， 受体AMD转换器然后转化为下游变化， 阿片介导的第二信使系统。在第一种情况下， 将通过[35/S] GTP γ S探索G蛋白受体的作用 放射自显影，它提供了神经解剖定位的 G蛋白受体的激活。因为这种技术允许 脑中同时测定的不同受体数量 从相同的动物切片，这提供了一个理想的方法， 有效地分析来自中心的动物的脑组织。这个项目 之前的研究表明，长期使用吗啡 治疗产生μ阿片样物质激活的G蛋白的选择性衰减 在特定的脑干核团中。这些研究将决定时间进程 的慢性吗啡效应，并将大鼠的慢性治疗与 吗啡与其他不同阿片类激动剂的长期治疗 效力和功效。对非偶然慢性 注射吗啡。为了确定G受体的这些变化， 蛋白偶联影响阿片第二信使系统， 同样的方法将分析毛喉素的阿片样物质抑制， 刺激脑啡肽原信号转导系统。第二 目的将检查长期服用可卡因和其他药物的影响， 受体偶联G蛋白的精神兴奋剂，特别关注 D2多巴胺受体、5-HT/1A受体和阿片受体。到 确定转运蛋白选择性和药代动力学对 受体偶联G蛋白的调节，合成新的托烷 由该中心与明确界定的具体性和行动的持续时间将 长期服用。该项目将使用获得的信息 从其他中心项目的规划研究，并提供 关于慢性药物治疗期间受体变化的信息， 对其他项目的研究很重要。