Animal Models of Fear and Anxiety

恐惧和焦虑的动物模型

• 批准号: 7553551
• 负责人: MICHAEL NMN DAVIS
• 金额: $ 15.96万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-29 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7553551
• 关键词: Agonist; Amygdaloid structure; Animal Model; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Behavior; Behavioral Assay; Behavioral Model; Bupropion; CRF receptor type 1; Cell Nucleus; Clinical; Corticotropin-Releasing Hormone; Cues; Dose; Evaluation; Female; Fostering; Fright; Gender; Goals; Human; Infusion procedures; Laboratories; Light; Lighting; Mediating; Modeling; Mood Disorders; Pharmaceutical Preparations; Rattus; Shock; Structure of terminal stria nuclei of preoptic region; Woman; male; men; novel; novel strategies; phosphodiesterase IV; response

Five compounds (the CRH1 receptor antagonist SB723620, the NK1 antagonist G597599, the SSRI/5HT2A agonist Vilazodone, the antidepressant 8-hydroxy-bupropion, and the type 4 phosphodiesterase inhbitor SB207499), provided by GlaxoSmithKline as part of The Emory-GSK-NIMH Collaborative Mood Disorders Initiative, will be evaluated for anti-fear and anxiolytic activity using fear-potentiated, light-enhanced, and CRH-enhanced startle paradigms (increased startle in the presence of cues that predict shock, during sustained illumination, or following i.c.v. corticotropin-releasing hormone infusions, respectively). Whereas light- and CRH-enhanced startle (which are more akin to anxiety than to fear) are mediated by circuitry that includes the bed nucleus of the stria terminalis (BNST) but not the central nucleus of the amygdala (CeA), fear-potentiated startle is mediated by circuitry that includes the CeA but not the BNST. A central goal of the proposed studies will be to identify differing pharmacological vulnerabilities associated with BNST (anxiety) versus CeA (fear) dependent behaviors. In humans, anxiety disorders are more prevalent in women than in men and, in rats, light-enhanced startle is more robust in females than in males. Interestingly, the BNST is sexually dimorphic in both species. Thus, a second goal will be to compare the influence of gender on BNST- versus CeA-dependent responses, and to evaluate gender influences on drug responses in each model. These same compounds will be evaluated in other laboratories (separate applications) using different behavioral models and non-behavioral assays. It is hoped that this integrated effort will foster new approaches for the rapid evaluation of novel compounds with potential clinical utility.

五种化合物（CRH1 受体拮抗剂 SB723620、NK1 拮抗剂 G597599、 SSRI/5HT2A 激动剂维拉佐酮、抗抑郁药 8-羟基安非他酮和 4 型 磷酸二酯酶抑制剂 SB207499）由葛兰素史克提供，作为埃默里 - 葛兰素史克 - NIMH 合作情绪障碍计划的一部分，将使用恐惧增强、光增强和 CRH 增强惊吓范例（增加惊吓）来评估其抗恐惧和抗焦虑活性。在存在预测休克的线索的情况下、在持续照明期间或在静脉注射后分别输注促肾上腺皮质激素释放激素）。光和 CRH 增强的惊吓（更类似于焦虑而不是恐惧）是由包括终纹床核 (BNST) 但不包括杏仁核中央核 (CeA) 的电路介导的，而恐惧增强惊吓是由包含 CeA 但不包含 BNST 的电路介导的。拟议研究的中心目标是确定与 BNST（焦虑）和 CeA（恐惧）依赖行为相关的不同药理学脆弱性。在人类中，焦虑症在女性中比在男性中更为普遍，而在老鼠中，光增强的焦虑症则更常见。 女性的惊吓比男性更强烈。有趣的是，两个物种的 BNST 都是两性异形的。因此，第二个目标是比较性别对 BNST 依赖性反应和 CeA 依赖性反应的影响，并评估每个模型中性别对药物反应的影响。这些相同的化合物将在其他实验室（单独的应用）使用不同的行为模型和非行为测定进行评估。希望这种综合努力将促进快速评估具有潜在临床实用性的新型化合物的新方法。