Translating Extinction of Fear to Anxiety Disorder Treatment

描述（由申请人提供）：恐惧消除，即通过重复提示（CS）暴露来减少条件性恐惧，长期以来一直是人类焦虑障碍行为治疗的明确模型。本R21应用程序的目的是加强该模型的证据，并测试最近在啮齿动物灭绝方面的几项发现的转化潜力。为了更好地建立啮齿动物恐惧消退模型的实用性，我们建议在恐惧条件小鼠、恐惧条件正常人和焦虑障碍患者三组中进行一系列平行研究。我们将进行第一次比较，以测试小鼠的恐惧消退机制是否与恐惧条件的人类相似。我们将进行第二次比较，以测试正常人类受试者条件恐惧的消退是否与人类焦虑障碍患者慢性恐惧的消退相似。我们将在两个具体目标中使用这种平行方法。在目标1中，我们将研究预期在灭绝中的作用。在受恐惧制约的人类和小鼠中，我们将在训练期间和灭绝期间操纵CS的相对长度，以创建提示呈现，这些提示呈现将或不会否定对不良事件的预期。在恐惧症患者中，我们将使用他们对期望的主观评分来创建这种不确定或不确定的暴露。在所有的人体实验中，我们将监测主观期望和心率、皮肤电导和眨眼惊吓等生理变量，以寻求有效产生灭绝的不确认暴露的可靠相关性。在目标2中，我们将研究激发在产生消光中的作用。基于在灭绝过程中增加的兴奋或恐惧会产生更大的灭绝这一假设，我们测试了增加恐惧的行为和药理学方法。在心理学上，我们将通过在小鼠和正常人身上独立条件线索的化合物来增加兴奋。药理学上，我们将在小鼠身上使用多种致焦虑化合物。在证明育亨宾（一种致焦虑的α 2肾上腺素能拮抗剂）加速小鼠的灭绝后，我们将测试育亨宾单独使用以及与认知增强剂d-环丝氨酸联合使用在有恐惧条件的人和焦虑症患者中的效果。这些实验应该有助于建立消除模型在焦虑障碍治疗中的翻译有效性，也可能对目前的焦虑障碍治疗产生潜在的改进。

DESCRIPTION (provided by applicant): Fear extinction, the reduction of conditional fear by repeated cue (CS) exposure, has long been the explicit model of behavior therapy for human anxiety disorders. The goals of this R21 application are both to strengthen the evidence for this model and to test the translational potential of several recent findings in rodent extinction. In order to better establish the utility of the model of rodent fear extinction, we propose to perform a series of parallel studies in three groups: fear conditioned mice, fear conditioned normal human subjects, and patients with anxiety disorder. We will perform the first comparison to test whether the mechanisms of fear extinction in mice parallel those in fear-conditioned humans. We will perform the second comparison to test whether extinction of conditioned fear in normal human subjects is similar to the extinction of chronic fears in human anxiety disorder patients. We will use this parallel approach in two specific Aims. In Aim 1 we will investigate the role of expectancy in extinction. In fear conditioned humans and mice, we will manipulate the relative lengths of CS used during training and during extinction to create cue presentations that will or will not disconfirm the expectation of an adverse event. In phobic patients, we will use their subjective ratings of expectancy to create such disconfirming or non-disconfirming exposures. Throughout all the human experiments we will monitor both subjective expectancy and physiological variables of heart rate, skin-conductance and eyeblink startle, to seek reliable correlates of disconfirming exposures that effectively generate extinction. In Aim 2 we will investigate the role of excitation in generating extinction. Based on the hypothesis that increased excitation, or fear, during extinction will yield greater extinction, we test both behavioral and pharmacological means of increasing fear. Psychologically, we will increase excitation through compounds of independently conditioned cues in mice and normal human subjects. Pharmacologically, we will use a variety of anxiogenic compounds in mice. Having shown that yohimbine, an anxiogenic alpha2 adrenergic antagonist, accelerates extinction in mice, we will test the effects of yohimbine alone and in combination with the cognitive enhancer, d-cycloserine, in fear-conditioned human beings and anxiety disorder patients. These experiments should help establish the translational validity of the extinction model for anxiety disorder treatment and also may yield potential improvements in current anxiety disorder treatments.