Animal Models of Fear and Anxiety

5个化合物（CRH 1受体拮抗剂SB 723620、NK 1拮抗剂G597599、 SSRI/5 HT 2A激动剂维拉唑酮、抗抑郁药8-羟基安非他酮和4型 磷酸二酯酶抑制剂SB 207499），由GlaxoSmithKline提供作为Emory-GSK-NIMH Collaborative Mood Disorders Initiative的一部分，将使用恐惧增强、光增强和CRH增强的惊吓范式（分别在存在预测休克的线索时、持续光照期间或i. c. v.促肾上腺皮质激素释放激素输注后增加惊吓）评估抗恐惧和抗焦虑活性。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）而不是杏仁核中央核（CeA）的回路介导的，而恐惧增强的惊吓是由包括CeA而不是BNST的回路介导的。拟议研究的一个中心目标是确定与BNST（焦虑）与CeA（恐惧）依赖行为相关的不同药理学脆弱性。在人类中，焦虑症在女性中比男性更普遍，在大鼠中， 女性比男性更容易受到惊吓。有趣的是，BNST在两个物种中都是性二型的。因此，第二个目标将是比较性别对BNST与CeA依赖性反应的影响，并评价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（单独应用）使用不同的行为模型和非行为分析进行评价。希望这种综合努力将促进新的方法，快速评估具有潜在临床实用性的新型化合物。

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.