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: 6410227
• 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: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6410227
• 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，以及几种滥用药物，都通过 与属于G蛋白偶联超家族的受体结合 感受器。这些药物包括阿片类药物，它直接作用于 自己的G蛋白受体和可卡因，它增加了突触外 与自身受体结合的多巴胺。这个项目的目标是 利用该中心提供的动物模型检查慢性 阿片类药物和精神刺激剂治疗影响不同类型的偶联 大脑中G蛋白的受体，以及这些变化是如何在 然后受体和转导蛋白翻译成下游的变化。 阿片类药物介导的第二信使系统。在第一种情况下，联轴器 G蛋白受体的研究将由[35/S]GTP GammaS探索 放射自显影，它提供了一个神经解剖学定位 激活G蛋白受体。因为这项技术允许 在大脑中同时检测不同受体的数量 来自相同动物的切片，这提供了一种理想的方法 高效地分析来自中心来源动物的脑组织。这个项目 将跟进之前的研究，这些研究表明慢性吗啡 治疗对Mu阿片激活的G蛋白的选择性抑制作用 在特定的脑干核团中。这些研究将确定时间进程 慢性吗啡的影响，并比较慢性治疗大鼠和 吗啡与其他阿片类激动剂对慢性治疗的不同 效力和效力。对非偶然性慢性疾病的影响 注射吗啡。以确定受体-G-的这些变化是如何- 蛋白质偶联影响阿片第二信使系统，治疗大鼠 同样的方法将分析阿片类药物对Forsklin的抑制作用- 体内刺激脑啡肽原信号转导系统。一秒钟 AIM将检查长期服用可卡因和其他药物的影响 受体偶联G蛋白上的精神刺激剂 在D2多巴胺受体、5-羟色胺/1A受体和阿片受体上。至 确定转运体选择性和药代动力学的影响 受体偶联对G蛋白的调节作用--合成新的托烷 由中心以明确的具体情况和行动持续时间 要长期给药。该项目将使用获得的信息 从中心的其他项目中计划其研究，并提供 有关慢性药物治疗期间受体变化的信息将 对其他项目的学习很重要。