Translating Extinction of Fear to Anxiety Disorder Treatment

描述(申请人提供)：恐惧消退，通过重复线索(CS)暴露减少条件性恐惧，长期以来一直是人类焦虑症行为治疗的明确模式。R21应用的目的既是为了加强这一模型的证据，也是为了测试最近在啮齿动物灭绝方面的几个发现的翻译潜力。为了更好地建立啮齿动物恐惧消退模型的实用性，我们建议在三组中进行一系列平行研究：恐惧条件化小鼠、恐惧条件化正常人和焦虑症患者。我们将进行第一次比较，以测试老鼠的恐惧消退机制是否与恐惧条件下的人类相似。我们将进行第二次比较，以测试正常人的条件性恐惧的消退是否类似于人类焦虑症患者的慢性恐惧的消退。我们将在两个具体目标中使用这种并行方法。在目标1中，我们将调查预期在物种灭绝中的作用。在恐惧条件化的人类和小鼠中，我们将操纵在训练和灭绝期间使用的CS的相对长度，以创建将或将不会否定对不良事件的预期的线索呈现。在恐惧症患者中，我们将使用他们对预期的主观评级来创造这种不确定或不确定的暴露。在所有的人体实验中，我们将监测心率、皮肤电导和眨眼惊吓的主观预期和生理变量，以寻找可靠的关联，寻找不确定的暴露，有效地产生灭绝。在目标2中，我们将研究激发在产生灭绝中的作用。基于这样一种假设，即在灭绝期间增加兴奋或恐惧会导致更大的灭绝，我们测试了增加恐惧的行为和药物方法。在心理学上，我们会在老鼠和正常人身上通过合成独立的条件性线索来增加兴奋。从药理上讲，我们将在小鼠身上使用多种引起焦虑的化合物。育亨宾是一种引起焦虑的α2肾上腺素能拮抗剂，在证明它能加速小鼠的衰老后，我们将测试育亨宾单独使用以及与认知增强剂d-环丝氨酸联合使用对患有恐惧症的人和焦虑症患者的效果。这些实验应该有助于建立焦虑症治疗的消退模型的翻译有效性，也可能在目前的焦虑症治疗中产生潜在的改进。

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.