Animal Models of Fear and Anxiety

5个化合物(CRH1受体拮抗剂SB723620，NK1拮抗剂G597599， SSRI/5HT2A激动剂维拉唑酮、抗抑郁剂8-羟基安非他酮和4型 作为Emory-GSK-NIMH协作情绪障碍计划的一部分，GlaxoSmithKline提供的磷酸二酯酶抑制剂SB207499将使用恐惧增强、光线增强和CRH增强的惊吓范例(在预测休克的提示存在时、在持续光照期间或在I.C.V.之后)来评估抗恐惧和缓解焦虑的活性。分别输注促肾上腺皮质激素释放激素)。光和CRH增强的惊吓(与其说是恐惧，不如说是焦虑)是由包括终纹床核(BNST)而不是杏仁中央核(CEA)的回路介导的，而恐惧强化的惊吓是由包括CEA但不包括BNST的回路介导的。拟议研究的中心目标将是确定与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普遍，在老鼠身上，光增强 雌性的惊吓比雄性的更强壮。有趣的是，BNST在两个物种中都是性别二态的。因此，第二个目标将是比较性别对BNST依赖反应和CEA依赖反应的影响，并在每个模型中评估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(单独应用)使用不同的行为模型和非行为分析进行评估。希望这一综合努力将促进具有潜在临床用途的新化合物的快速评估的新方法。

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.