Project 4: Effects of CRF1 recoptor antagonists and other putative antidepressant

这项建议是一个综合项目的一部分，该项目旨在测试三种候选抗焦虑药物(两种 结构无关的CRR受体拮抗剂GSK008和CRF-002，以及5HTiA/IB/io受体 拮抗剂GSK-1，由葛兰素史克(GSK)提供，作为Emory-MSSM-GSK-NIMH的一部分 合作情绪障碍倡议，使用恐惧强化的惊吓。丹参的抗恐惧和抗焦虑活性 这些化合物将在健康受试者中使用阶段(恐惧)和持续(焦虑)模型进行评估。 厌恶状态源于人类和啮齿动物的临床前研究。两个实验模型将 一种是基于指示的恐惧学习程序，另一种是使用巴甫洛夫线索 以及计算机生成的虚拟现实环境中的上下文条件作用，这也将使我们能够 检查行为回避。这两种程序都是为了区分阶段性恐惧和 持续性焦虑，根据临床前研究(戴维斯博士，项目1)，这种焦虑是由不同的 神经系统。我们将研究在预期无休克、可预测休克的过程中惊吓的增强作用 由离散的威胁提示和不可预测的冲击发出信号。恐惧强化的惊吓对离散的威胁提示 将模拟阶段性恐惧，而惊吓在可预测和不可预测的冲击中的增强 条件将为持续的情境焦虑提供模型。该项目的一个中心目标是检查 在这些模型中，GSK化合物具有抗焦虑作用，已被证明可以检测到GSK的抗焦虑活性 已确定的抗焦虑药物(阿普唑仑、苯二氮卓类药物和艾司匹林和SSRI)。另一个目标是确定 阶段性恐惧与持续性焦虑的不同心理药理学特征。鉴于……的流行 女性焦虑症与男性相比，一个探索性的目标将是检查性别差异 存在关于我们的焦虑模型对GSK化合物治疗的敏感性的问题。 这些相同的葛兰素史克化合物也将在其他实验室进行评估(项目1和5)(单独 应用)，为筛选和评估新化合物的功效提供了一种翻译方法。 戴维斯博士的临床前项目(项目1)，特别是对本项目的补充，将使用 啮齿动物的类似行为模型基于惊吓，作为衡量恐惧和焦虑的操作指标。戴维斯博士。 Rothbaum和Charney的项目(项目5)将测试GSK008对创伤后应激的临床疗效 无序。这些平行项目将对人类和动物模型的预测有效性进行测试。 希望这一综合努力最终将导致开发和验证快速的模型 对新疗法的评价。

This proposal is a part of an integrated project to test the efficacy of three candidate anxiolytics (two structurally unrelated CRr-^ receptor antagonists GSK008 and CRF-002, and a 5HTiA/iB/io receptor antagonist, GSK-1, provided by GlaxoSmithKline (GSK) as part of The Emory-MSSM-GSK-NIMH Collaborative Mood Disorders Initiative, using fear-potentiated startle. The anti-fear and anxiolytic activity of these compounds will be evaluated in healthy subjects using models of phasic (fear) and sustained (anxiety) aversive states derived from humans and from pre-clinical studies in rodents. Two experimental models will be implemented; one based on an instructed fear learning procedure and the other using Pavlovian cued and context conditioning in a computer-generated virtual reality environment, which will also enable us to examine behavioral avoidance. Both procedures are designed to distinguish between phasic fear and sustained anxiety, which according to pre-clinical studies (Dr. Davis, Project 1) are mediated by distinct neural systems. We will examine the potentiation of startle during anticipation of no-shock, predictable shock signaled by a discrete threat cue, and unpredictable shock. Fear-potentiated startle to the discrete threat cue will model phasic fear, whereas the potentiation of startle in the predictable and unpredictable shock conditions will model sustained contextual anxiety. A central goal of this project is to examine whether the GSK compounds are anxiolytic in these models, which have been shown to detect the anxiolytic activity of established anxiolytics (alprazolam, a benzodiazepine, and escitalopram an SSRI). Another goal is to identify different psychopharmacological profiles for phasic fear versus sustained anxiety. Given the prevalence of anxiety disorders in women compared to men, an exploratory aim will be to examine whether sex differences exist with respect to the sensitivity of our anxiety model to treatment with the GSK compounds. These same GSK compounds will also be evaluated in other laboratories (Projects 1 and 5) (separate applications), providing a translational approach to screening and evaluating the efficacy of new compounds. Dr. Davis' preclinical project (Project 1), which is particularly complementary to the present project, will use similar behavioral models in rodents based on startle as an operational measure of fear and anxiety. Drs. Rothbaum and Charney's project (Project 5) will test the clinical efficacy of GSK008 in posttraumatic stress disorder. These parallel projects will provide a test of the predictive validity of the human and animal models. It is hoped that this integrated effort will ultimately lead to development and validation of models for rapid evaluation of novel therapeutics.