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（SSRIs）是治疗糖尿病最有效的方法之一