Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
Laboratory of Addictive Disorders, Departments of Pharmacology and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
Neuropharmacology. 2019 Dec 1;160:107761. doi: 10.1016/j.neuropharm.2019.107761. Epub 2019 Sep 4.
Anxiety-related disorders are the most prevalent mental disorders in the world and they are characterized by abnormal responses to stressors. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide highly expressed in the extended amygdala, a brain macrostructure involved in the response to threat that includes the central nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). The aim of this series of experiments was to systematically elucidate the role of the PACAP system of the CeA and BNST under both control, unstressed conditions and after the presentation of a stressor in rats. For this purpose, we used the acoustic startle response (ASR), an unconscious response to sudden acoustic stimuli sensitive to changes in stress which can be used as an operationalization of the hypervigilance present in anxiety- and trauma-related disorders. We found that infusion of PACAP, but not the related peptide vasoactive intestinal peptide (VIP), into either the CeA or the BNST causes a dose-dependent increase in ASR. In addition, while infusion of the antagonist PACAP(6-38) into either the CeA or the BNST does not affect ASR in non-stressed conditions, it prevents the sensitization of ASR induced by an acute footshock stress. Finally, we found that footshock stress induces a significant increase in PACAP, but not VIP, levels in both of these brain areas. Altogether, these data show that the PACAP system of the extended amygdala contributes to stress-induced hyperarousal and suggest it as a potential novel target for the treatment of stress-related disorders.
焦虑相关障碍是世界上最普遍的精神障碍，其特征是对压力源的异常反应。垂体腺苷酸环化酶激活肽（PACAP）是一种在扩展杏仁核中高度表达的神经肽，扩展杏仁核是一种参与威胁反应的大脑宏观结构，包括杏仁核中央核（CeA）和终纹床核（BNST）。本系列实验的目的是系统阐明 CeA 和 BNST 中的 PACAP 系统在应激前和应激后大鼠的正常和应激条件下的作用。为此，我们使用了听觉惊跳反应（ASR），这是一种对突然听觉刺激的无意识反应，对压力变化敏感，可作为焦虑和创伤相关障碍中过度警惕的操作性定义。我们发现，PACAP 而不是相关肽血管活性肠肽（VIP）注入 CeA 或 BNST 都会引起 ASR 的剂量依赖性增加。此外，虽然 PACAP(6-38)注入 CeA 或 BNST 在非应激条件下不影响 ASR，但它可防止急性足底电击应激引起的 ASR 敏化。最后，我们发现足底电击应激会导致这两个脑区中的 PACAP 而不是 VIP 水平显著增加。总之，这些数据表明扩展杏仁核中的 PACAP 系统有助于应激引起的过度觉醒，并表明其可能成为治疗应激相关障碍的新靶点。
