Project 1: Rat Models of Anxiety

项目1：大鼠焦虑模型

• 批准号: 8112728
• 负责人: Michael E Davis
• 金额: $ 37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112728
• 关键词: Acoustics; Acute; Adverse effects; Affect; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Area; Brain; CRF receptor type 1; Cell Nucleus; Chronic; Clinical; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Development; Dose; Escitalopram; Fright; Goals; Grant; Lentivirus Vector; Measures; Mediating; Mental Depression; Modeling; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Rat-1; Rattus; Regimen; Selective Serotonin Reuptake Inhibitor; Stimulus; Testing; Time; Training; Treatment Failure; Uncertainty; Work; clinical anxiety; comparative efficacy; conditioned fear; effective therapy; novel; overexpression; receptor; relating to nervous system; release factor; response; tool

Selective serotonin reuptake inhibitors (SSRIs) are among the most effective treatments for the pharmacological treatment of clinical anxiety. However, meaningful clinical improvements do not occur for several weeks in most patients and not at all in others. Moreover, a great deal of uncertainty exists as to how these compounds actually work. A significant obstacle to understanding the mechanism of clinical action, and to developing more efficacious and rapid-acting treatments, has been the lack of validated animal models of SSRI-sensitive anxiety. Over the last several years, we have obtained evidence that sustained increases in the amplitude of the acoustic startle response in response to long-duration threat stimuli are mediated by brain areas different from those which mediate shorter-duration phasic increases. The former type of response seems more akin to anxiety than to fear, and may be more suitable for detecting SSRImediated anxiolysis. Findings during the last grant period indicate that sustained startle increases are especially sensitive to corticotropin releasing factor type 1 receptor (CRF-R1) antagonists. In this application we will 1) compare the anxiolytic activity of two CRF-R1 receptor antagonists (GSK008 and CRF-002) in the sustained fear test; determine if sensitivity to CRF-R1 receptor blockade depends on conditioned fear stimulus duration during training or, alternatively, response duration during testing; and determine with greater precision the time-course over which potentiated startle becomes CRF-dependent, 2) Compare the efficacy and time-course of a mixed 5HTiA/iB/iD receptor antagonist (GSK-1) with that of the selective serotonin reuptake inhibitor (SSRI) escitalopram in disrupting phasic versus sustained fear, after acute versus chronic administration, 3) Evaluate the effect of acute versus chronic administration of GSK-1 and escitalopram in blocking CRF-enhanced startle and the effect of the CRF! receptor antagonist, GSK008, on the acute anxiogenic effects of escitalopram, 4) Evaluate over-expression of CRF in the central nucleus of the amygdala (CeA), using a CRF-producing lentiviral vector, as a novel model of anxiety in rats, and evaluate the effect of GSK008, CRF-002 and chronic administration of GSK-1 and escitalopram on measures of anxiety in these animals

选择性血清素再摄取抑制剂（SSRI）是治疗该病最有效的药物之一 临床焦虑症的药物治疗。然而，有意义的临床改善并未发生 大多数患者需要几周的时间，而其他患者则完全不会。此外，如何实现这一点还存在很大的不确定性。 这些化合物确实有效。理解临床作用机制的一个重大障碍， 以及开发更有效和快速起效的治疗方法，一直缺乏经过验证的动物 SSRI 敏感焦虑模型。在过去的几年里，我们获得的证据表明 响应长时间威胁刺激的声音惊恐反应幅度的增加是 由与介导较短持续时间阶段性增加的大脑区域不同的大脑区域介导。前者 反应类型似乎更类似于焦虑而不是恐惧，并且可能更适合检测 SSRI 介导的 抗焦虑。上一次拨款期间的调查结果表明，持续的惊人增加是 对促肾上腺皮质激素释放因子 1 型受体 (CRF-R1) 拮抗剂特别敏感。在这个应用程序中 我们将 1) 比较两种 CRF-R1 受体拮抗剂（GSK008 和 CRF-002）的抗焦虑活性 持续恐惧测试；确定对 CRF-R1 受体阻断的敏感性是否取决于条件性恐惧 训练期间的刺激持续时间，或者测试期间的反应持续时间；并确定 更精确地表示强化惊吓变得依赖于 CRF 的时间过程，2) 比较 混合 5HTiA/iB/iD 受体拮抗剂 (GSK-1) 与选择性 5HTiA/iB/iD 受体拮抗剂 (GSK-1) 的功效和时程 血清素再摄取抑制剂（SSRI）艾司西酞普兰在扰乱急性发作后的阶段性恐惧与持续性恐惧中的作用 与长期给药相比，3) 评估急性与长期给药 GSK-1 的效果，以及 艾司西酞普兰在阻断CRF增强惊吓和CRF方面的效果！受体拮抗剂，GSK008， 艾司西酞普兰的急性致焦虑作用，4) 评估 CRF 在中央核中的过度表达 杏仁核 (CeA)，使用产生 CRF 的慢病毒载体，作为大鼠焦虑的新型模型，以及 评估 GSK008、CRF-002 以及长期服用 GSK-1 和艾司西酞普兰对 这些动物的焦虑措施