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5-羟色胺再摄取抑制剂（SSRI）是最有效的治疗方法之一 临床焦虑的药理治疗。但是，没有进行有意义的临床改进 在大多数患者中，几个星期都不是其他患者。而且，关于如何 这些化合物实际上起作用。了解临床作用机制的重要障碍， 并且要开发更有效和快速的疗法，这是缺乏经过验证的动物 SSRI敏感焦虑的模型。在过去的几年中，我们获得了持续的证据 响应长期威胁刺激的声音惊吓幅度的增加是 由大脑区域介导的与介导较短的阶段增加的大脑区域介导的。前者 反应的类型似乎更像焦虑，而不是恐惧，可能更适合于检测SSRIMIDISED 抗焦解。在上一个赠款期间的调查结果表明，持续的惊吓增加是 对皮质激素释放因子1型受体（CRF-R1）拮抗剂特别敏感。在此应用程序中 我们将1）比较两个CRF-R1受体拮抗剂（GSK008和CRF-002）的抗焦虑活性 持续的恐惧测试；确定对CRF-R1受体阻滞的敏感性是否取决于条件恐惧 训练期间的刺激持续时间或测试过程中的响应持续时间；并确定 更精确的时间顺序与增强的惊吓变得依赖CRF的时间顺序，2）比较 混合5HTIA/IB/ID受体拮抗剂（GSK-1）的功效和时间顺序与选择性 血清素再摄取抑制剂（SSRI）在急性之后破坏阶段与持续的恐惧中苏联依他普兰 对慢性给药，3）评估急性对GSK-1和慢性给药的影响 苏联阻塞CRF增强的惊吓和CRF的影响！受体拮抗剂GSK008，ON 依他普兰的急性焦虑作用，4）评估CRF的过表达在中央核中 使用CRF产生的慢病毒载体作为大鼠焦虑的新模型，杏仁核（CEA）和 评估GSK008，CRF-002和GSK-1和Escitalopram的长期给药的影响 这些动物的焦虑措施