Department of Pharmacology, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2009 Dec 31;4(12):e8528. doi: 10.1371/journal.pone.0008528.
Stress is a complex human experience and having both rewarding and aversive motivational properties. The adverse effects of stress are well documented, yet many of underlying mechanisms remain unclear and controversial. Here we report that the anxiogenic properties of stress are encoded by the endogenous opioid peptide dynorphin acting in the basolateral amygdala. Using pharmacological and genetic approaches, we found that the anxiogenic-like effects of Corticotropin Releasing Factor (CRF) were triggered by CRF(1)-R activation of the dynorphin/kappa opioid receptor (KOR) system. Central CRF administration significantly reduced the percent open-arm time in the elevated plus maze (EPM). The reduction in open-arm time was blocked by pretreatment with the KOR antagonist norbinaltorphimine (norBNI), and was not evident in mice lacking the endogenous KOR ligand dynorphin. The CRF(1)-R agonist stressin 1 also significantly reduced open-arm time in the EPM, and this decrease was blocked by norBNI. In contrast, the selective CRF(2)-R agonist urocortin III did not affect open arm time, and mice lacking CRF(2)-R still showed an increase in anxiety-like behavior in response to CRF injection. However, CRF(2)-R knockout animals did not develop CRF conditioned place aversion, suggesting that CRF(1)-R activation may mediate anxiety and CRF(2)-R may encode aversion. Using a phosphoselective antibody (KORp) to identify sites of dynorphin action, we found that CRF increased KORp-immunoreactivity in the basolateral amygdala (BLA) of wildtype, but not in mice pretreated with the selective CRF(1)-R antagonist, antalarmin. Consistent with the concept that acute stress or CRF injection-induced anxiety was mediated by dynorphin release in the BLA, local injection of norBNI blocked the stress or CRF-induced increase in anxiety-like behavior; whereas norBNI injection in a nearby thalamic nucleus did not. The intersection of stress-induced CRF and the dynorphin/KOR system in the BLA was surprising, and these results suggest that CRF and dynorphin/KOR systems may coordinate stress-induced anxiety behaviors and aversive behaviors via different mechanisms.
压力是一种复杂的人类体验，具有奖励和厌恶的动机特性。压力的不良影响已有充分记录，但许多潜在机制仍不清楚且存在争议。在这里，我们报告说，内源性阿片肽强啡肽在外侧杏仁核中的作用编码了压力的焦虑特性。通过药理学和遗传学方法，我们发现促肾上腺皮质释放因子 (CRF) 的类似焦虑作用是由 CRF(1)-R 激活强啡肽/κ 阿片受体 (KOR) 系统触发的。中枢 CRF 给药显著减少高架十字迷宫 (EPM) 中的开臂时间百分比。KOR 拮抗剂诺宾那肽 (norBNI) 的预处理可阻断开臂时间的减少，而在缺乏内源性 KOR 配体强啡肽的小鼠中则不明显。CRF(1)-R 激动剂 stressin 1 也显著减少 EPM 中的开臂时间，并且这种减少被 norBNI 阻断。相比之下，选择性 CRF(2)-R 激动剂 Urocortin III 不会影响开臂时间，并且缺乏 CRF(2)-R 的小鼠在对 CRF 注射的反应中仍表现出焦虑样行为增加。然而，CRF(2)-R 敲除动物不会产生 CRF 条件性位置厌恶，这表明 CRF(1)-R 激活可能介导焦虑，而 CRF(2)-R 可能编码厌恶。使用磷酸选择性抗体 (KORp) 来鉴定强啡肽作用的部位，我们发现 CRF 增加了野生型外侧杏仁核 (BLA) 中的 KORp-免疫反应性，但在预先用选择性 CRF(1)-R 拮抗剂 antalarmin 处理的小鼠中则没有。与急性应激或 CRF 注射诱导的焦虑是由 BLA 中的强啡肽释放介导的概念一致，局部注射 norBNI 阻断了应激或 CRF 诱导的焦虑样行为增加；而 norBNI 注射到附近的丘脑核则没有。BLA 中应激诱导的 CRF 和强啡肽/KOR 系统的交集令人惊讶，这些结果表明 CRF 和强啡肽/KOR 系统可能通过不同的机制协调应激诱导的焦虑行为和厌恶行为。
