Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats
Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats
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DOI：
10.1038/npp.2017.305
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发表时间：
2018-05-01
影响因子：
7.6
通讯作者：
Campolongo, Patrizia
中科院分区：
文献类型：
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作者：
Morena, Maria;Berardi, Andrea;Campolongo, Patrizia
暴露在创伤事件中可能会导致创伤后应激障碍(PTSD)的发展。内源性大麻素是应激反应的重要调节剂，干扰过度提取，促进创伤性记忆的消退。暴露疗法与药物疗法相结合，是治疗创伤后应激障碍的一种很有前途的工具。我们调查了在灭绝学习期间对内源性大麻素系统的药理操作是否改善了创伤暴露引起的行为变化。老鼠暴露在不可避免的脚踏电击中，并伴随着社会孤立，这是创伤后应激障碍的一个风险因素。创伤后一周，大鼠接受了三次间隔拔牙治疗，模拟人类暴露疗法。在消融前后分别给予苯乙酰胺水解抑制剂URB597、2-花生四烯基甘油水解抑制剂JZL184或大麻素激动剂WIN55、212-2。在创伤后16天或36天测试大鼠的消亡保持能力，并在24小时后进行社会交往测试。单独的消亡训练减少了对创伤相关环境的恐惧，但并不能恢复正常的社会互动。没有暴露在灭绝过程中的创伤动物显示出与家庭笼养的对照组相比，海马区贫血含量的减少。值得注意的是，所有药物都有有益的效果，但URB597(0.1 mg/kg)通过间接激活CBI受体，促进了创伤大鼠的灭绝巩固和恢复正常的社会行为，从而产生了最好的改善作用。在治疗和创伤暴露后很长时间内改善效果保持稳定。我们的发现表明，加强内源性大麻素神经传递的药物与基于暴露的心理疗法相结合，可能是治疗创伤后应激障碍的有前景的工具。
Exposure to a traumatic event may result in the development of post-traumatic stress disorder (PTSD). Endocannabinoids are crucial modulators of the stress response, interfere with excessive retrieval and facilitate the extinction of traumatic memories. Exposure therapy, combined with pharmacotherapy, represents a promising tool for PTSD treatment. We investigated whether pharmacological manipulations of the endocannabinoid system during extinction learning ameliorates the behavioral changes induced by trauma exposure. Rats were exposed to inescapable footshocks paired with social isolation, a risk factor for PTSD. One week after trauma, rats were subjected to three spaced extraction sessions, mimicking human exposure therapy. The anandamide hydrolysis inhibitor URB597, the 2-arachidonoylglycerol hydrolysis inhibitor JZL184 or the cannabnoid agonist WIN55,212-2 were administered before or after the extinction sessions. Rats were tested for extinction retention 16 or 36 days after trauma and 24-h later for social interaction. Extinction training alone reduced fear of the trauma-associated context but did not restore normal social interaction. Traumatized animals not exposed to extinction sessions exhibited reductions in hippocampal anandamide content with respect to home-cage controls. Noteworthy, all drugs exerted beneficial effects, but URB597 (0.1 mg/kg) induced the best improvements by enhancing extinction consolidaton and restoring normal social behavior in traumatized rats through indirect activation of CBI receptors. The ameliorating effects remained stable long after treatment and trauma exposure. Our findings suggest that drugs potentiating endocannabinoid neurotransmission may represent promising tools when combined to exposure-based psychotherapies in the treatment of PTSD.