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Enhancing Endocannabinoid Neurotransmission Augments The Efficacy of Extinction Training and Ameliorates Traumatic Stress-Induced Behavioral Alterations in Rats.
Neuropsychopharmacology ( IF 7.6 ) Pub Date : 2018-05-01 , DOI: 10.1038/npp.2017.305 Maria Morena , Andrea Berardi , Paola Colucci , Maura Palmery , Viviana Trezza , Matthew N Hill , Patrizia Campolongo
Neuropsychopharmacology ( IF 7.6 ) Pub Date : 2018-05-01 , DOI: 10.1038/npp.2017.305 Maria Morena , Andrea Berardi , Paola Colucci , Maura Palmery , Viviana Trezza , Matthew N Hill , Patrizia Campolongo
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 extinction sessions, mimicking human exposure therapy. The anandamide hydrolysis inhibitor URB597, the 2-arachidonoylglycerol hydrolysis inhibitor JZL184 or the cannabinoid 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 consolidation and restoring normal social behavior in traumatized rats through indirect activation of CB1 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.
中文翻译:
增强内源性大麻素神经传递的增强灭绝训练的功效和减轻大鼠创伤性应激引起的行为改变。
暴露于创伤事件可能会导致创伤后应激障碍(PTSD)的发展。内源性大麻素是压力反应的关键调节剂,会干扰过度恢复并促进创伤性记忆的消失。暴露疗法与药物疗法的结合代表了PTSD治疗的一种有前途的工具。我们调查了灭绝学习过程中内源性大麻素系统的药理作用是否改善了外伤暴露引起的行为变化。将大鼠暴露于不可避免的足底,并伴有社交隔离,这是PTSD的危险因素。创伤后一周,模拟人类暴露疗法,对大鼠进行了三个间隔的灭绝。花生四烯酸水解抑制剂URB597,在灭绝前或灭绝后施用2-花生四烯酰基甘油水解抑制剂JZL184或大麻素激动剂WIN55,212-2。在创伤后16或36天以及24小时后的社交互动中对大鼠进行灭绝保持测试。单独进行的灭绝训练减少了对与创伤有关的情况的恐惧,但并没有恢复正常的社交互动。相对于笼养对照,未暴露于灭绝阶段的创伤动物表现出海马安南酰胺含量降低。值得注意的是,所有药物均发挥有益作用,但URB597(0.1 mg / kg)通过增强灭绝巩固作用和通过间接激活CB1受体来恢复受创伤大鼠的正常社交行为,诱导了最佳的改善。在治疗和创伤暴露后很长时间,改善效果保持稳定。
更新日期:2017-12-21
中文翻译:
增强内源性大麻素神经传递的增强灭绝训练的功效和减轻大鼠创伤性应激引起的行为改变。
暴露于创伤事件可能会导致创伤后应激障碍(PTSD)的发展。内源性大麻素是压力反应的关键调节剂,会干扰过度恢复并促进创伤性记忆的消失。暴露疗法与药物疗法的结合代表了PTSD治疗的一种有前途的工具。我们调查了灭绝学习过程中内源性大麻素系统的药理作用是否改善了外伤暴露引起的行为变化。将大鼠暴露于不可避免的足底,并伴有社交隔离,这是PTSD的危险因素。创伤后一周,模拟人类暴露疗法,对大鼠进行了三个间隔的灭绝。花生四烯酸水解抑制剂URB597,在灭绝前或灭绝后施用2-花生四烯酰基甘油水解抑制剂JZL184或大麻素激动剂WIN55,212-2。在创伤后16或36天以及24小时后的社交互动中对大鼠进行灭绝保持测试。单独进行的灭绝训练减少了对与创伤有关的情况的恐惧,但并没有恢复正常的社交互动。相对于笼养对照,未暴露于灭绝阶段的创伤动物表现出海马安南酰胺含量降低。值得注意的是,所有药物均发挥有益作用,但URB597(0.1 mg / kg)通过增强灭绝巩固作用和通过间接激活CB1受体来恢复受创伤大鼠的正常社交行为,诱导了最佳的改善。在治疗和创伤暴露后很长时间,改善效果保持稳定。