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

该建议是一个综合项目的一部分，以测试三个候选抗焦虑药（两个 结构上不相关的CRr-10受体拮抗剂GSK 008和CRF-002，以及5 HT 1A/1B/10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 协作情绪障碍倡议，使用恐惧增强惊吓。的抗恐惧和抗焦虑活性 将使用阶段性（恐惧）和持续性（焦虑）模型在健康受试者中评价这些化合物， 来自人类和啮齿动物临床前研究的厌恶状态。两个实验模型将 一个基于指导的恐惧学习程序，另一个使用巴甫洛夫线索 以及计算机生成的虚拟现实环境中的情境调节，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 持续的焦虑，根据临床前研究（戴维斯博士，项目1）是由不同的介导 神经系统我们将研究在预期无电击、可预测的电击时惊吓的增强 由离散的威胁信号和不可预测的电击发出信号。对离散威胁线索的恐惧增强惊吓 将模拟阶段性恐惧，而在可预测和不可预测的冲击中， 条件将模拟持续的情境焦虑。该项目的一个中心目标是检查 GSK化合物在这些模型中是抗焦虑的，其已显示检测GSK化合物的抗焦虑活性。 已确立的抗焦虑药（阿普唑仑，一种苯二氮卓类药物，和艾司西酞普兰，一种SSRI）。另一个目标是确定 阶段性恐惧和持续性焦虑的不同心理药理学特征。鉴于普遍存在的 与男性相比，女性焦虑症的探索性目的将是检查性别差异是否 存在关于我们的焦虑模型对GSK化合物治疗的敏感性。 这些相同的GSK化合物也将在其他实验室（项目1和5）（单独）进行评价。 应用），提供了一种筛选和评估新化合物功效的转化方法。 博士Davis的临床前项目（项目1）对本项目特别有补充作用，将使用 啮齿类动物的类似行为模型基于惊吓作为恐惧和焦虑的操作措施。Drs. Rothbaum和Charney的项目（项目5）将测试GSK 008在创伤后应激中的临床疗效 disorder.这些平行项目将提供对人类和动物模型预测有效性的测试。 希望这一综合努力将最终导致开发和验证快速 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.