Department of Psychology, University of Haifa, Haifa, 3498838, Israel.
Hippocampus. 2017 Oct;27(10):1093-1109. doi: 10.1002/hipo.22755. Epub 2017 Jul 14.
Exposure to excessive or uncontrolled stress is a major factor associated with various diseases including posttraumatic stress disorder (PTSD). The consequences of exposure to trauma are affected not only by aspects of the event itself, but also by the frequency and severity of trauma reminders. It was suggested that in PTSD, hippocampal-dependent memory is compromised while amygdala-dependent memory is strengthened. Several lines of evidence support the role of the endocannabinoid (eCB) system as a modulator of the stress response. In this study we aimed to examine cannabinoids modulation of the long-term effects (i.e., 1 month) of exposure to a traumatic event on memory and plasticity in the hippocampus and amygdala. Following exposure to the shock and reminders model of PTSD in an inhibitory avoidance light-dark apparatus rats demonstrated: (i) enhanced fear retrieval and impaired inhibitory extinction (Ext), (ii) no long-term potentiation (LTP) in the CA1, (iii) impaired hippocampal-dependent short-term memory in the object location task, (iv) enhanced LTP in the amygdala, and (v) enhanced amygdala-dependent conditioned taste aversion memory. The cannabinoid CB1/2 receptor agonist WIN55-212,2 (0.5mg/kg, i.p.) and the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3mg/kg, i.p.), administered 2 hr after shock exposure prevented these opposing effects on hippocampal- and amygdala-dependent processes. Moreover, the effects of WIN55-212,2 and URB597 on Ext and acoustic startle were prevented by co-administration of a low dose of the CB1 receptor antagonist AM251 (0.5mg/kg, i.p.), suggesting that the preventing effects of both drugs are mediated by CB1 receptors. Exposure to shock and reminders increased CB1 receptor levels in the CA1 and basolateral amygdala 1 month after shock exposure and this increase was also prevented by administering WIN55-212,2 or URB597. Taken together, these findings suggest the involvement of the eCB system, and specifically CB1 receptors, in the opposite effects of severe stress on memory and plasticity in the hippocampus and amygdala.
暴露于过度或不受控制的压力是与各种疾病相关的主要因素，包括创伤后应激障碍（PTSD）。暴露于创伤的后果不仅受事件本身的各个方面影响，还受创伤提醒的频率和严重程度影响。有人认为，在 PTSD 中，海马体依赖的记忆受损，而杏仁核依赖的记忆增强。有几条证据支持内源性大麻素（eCB）系统作为应激反应调节剂的作用。在这项研究中，我们旨在检查大麻素对创伤事件暴露后记忆和海马体和杏仁核可塑性的长期影响（即 1 个月）的调节作用。在抑制性回避明暗装置中暴露于 PTSD 的休克和提醒模型后，大鼠表现出：（i）恐惧检索增强和抑制性消退（Ext）受损，（ii）CA1 中无长时程增强（LTP），（iii）物体位置任务中的海马体依赖的短期记忆受损，（iv）杏仁核中的 LTP 增强，以及（v）杏仁核依赖的条件味觉厌恶记忆增强。大麻素 CB1/2 受体激动剂 WIN55-212,2（0.5mg/kg，ip）和脂肪酸酰胺水解酶（FAAH）抑制剂 URB597（0.3mg/kg，ip），在休克暴露后 2 小时给予，可防止这些对海马体和杏仁核依赖过程的相反作用。此外，WIN55-212,2 和 URB597 对 Ext 和听觉惊吓的作用被共给予低剂量 CB1 受体拮抗剂 AM251（0.5mg/kg，ip）所阻止，表明这两种药物的预防作用均由 CB1 受体介导。暴露于休克和提醒会增加 CA1 和基底外侧杏仁核中 1 个月后休克暴露后的 CB1 受体水平，而给予 WIN55-212,2 或 URB597 也可防止这种增加。总之，这些发现表明内源性大麻素系统，特别是 CB1 受体，参与了严重应激对海马体和杏仁核中记忆和可塑性的相反作用。
