Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 1111 West 10th Street, Indianapolis, IN 46202, USA.
Physiol Behav. 2012 Dec 5;107(5):686-98. doi: 10.1016/j.physbeh.2012.03.016. Epub 2012 Mar 26.
Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute panic-like increases in cardioexcitation, respiration activity and "flight" associated behavior following subthreshold interoceptive stimuli that do not elicit panic responses in control rats. This model of panic vulnerability was developed over 15 years ago and has provided an excellent preclinical model with robust face, predictive and construct validity. The model recapitulates many of the phenotypic features of panic attacks associated with human panic disorder (face validity) including greater sensitivity to panicogenic stimuli demonstrated by sudden onset of anxiety and autonomic activation following an administration of a sub-threshold (i.e., do not usually induce panic in healthy subjects) stimulus such as sodium lactate, CO(2), or yohimbine. The construct validity is supported by several key findings; DMH/PeF neurons regulate behavioral and autonomic components of a normal adaptive panic response, as well as being implicated in eliciting panic-like responses in humans. Additionally, patients with PD have deficits in central GABA activity and pharmacological restoration of central GABA activity prevents panic attacks, consistent with this model. The model's predictive validity is demonstrated by not only showing panic responses to several panic-inducing agents that elicit panic in patients with PD, but also by the positive therapeutic responses to clinically used agents such as alprazolam and antidepressants that attenuate panic attacks in patients. More importantly, this model has been utilized to discover novel drugs such as group II metabotropic glutamate agonists and a new class of translocator protein enhancers of GABA, both of which subsequently showed anti-panic properties in clinical trials. All of these data suggest that this preparation provides a strong preclinical model of some forms of human panic disorders.
惊恐障碍（PD）是一种严重的焦虑障碍，其特征是对阈下内脏刺激（如乳酸盐输注或高碳酸血症诱导）易引发惊恐发作。在这里，我们回顾了一种在大鼠中易发生惊恐的模型，该模型涉及背内侧/peri 下丘脑（DMH/PeF）区域中 GABA 能张力的慢性抑制，该模型在恐惧情境中产生增强的焦虑和冻结反应，并且在阈下内脏刺激下容易出现急性类似惊恐的心血管兴奋、呼吸活动和“逃避”相关行为的增加，而这些刺激在对照大鼠中不会引发惊恐反应。这种易发生惊恐的大鼠模型是在 15 年前建立的，它提供了一个极好的临床前模型，具有强大的面部、预测性和构建效度。该模型再现了许多与人类惊恐障碍相关的惊恐发作的表型特征（面部效度），包括对惊恐刺激的更高敏感性，这表现为在给予阈下（即通常不会在健康受试者中引发惊恐）刺激（如乳酸盐、CO2 或育亨宾）后，焦虑和自主激活突然出现。该模型的构建效度得到了几个关键发现的支持；DMH/PeF 神经元调节正常适应性惊恐反应的行为和自主成分，并且与人类中引发类似惊恐的反应有关。此外，PD 患者的中枢 GABA 活性降低，中枢 GABA 活性的药理学恢复可预防惊恐发作，这与该模型一致。该模型的预测效度不仅通过显示对几种可引发 PD 患者惊恐发作的惊恐诱导剂的惊恐反应得到证明，还通过对临床使用的药物（如阿普唑仑和抗抑郁药）的阳性治疗反应得到证明，这些药物可减轻患者的惊恐发作。更重要的是，该模型已被用于发现新的药物，如 II 组代谢型谷氨酸能受体激动剂和一类新的 GABA 转运蛋白增强剂，它们在临床试验中均显示出抗惊恐作用。所有这些数据表明，该制剂为某些形式的人类惊恐障碍提供了一个强有力的临床前模型。
