Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.

中文翻译：

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内源性大麻素在海马和杏仁核在情绪记忆和可塑性中的作用。

创伤后应激障碍（PTSD）的特征是再次发生创伤事件，并与恐惧反应的消失较慢有关。对创伤相关线索的恐惧关联的绝种受损可能会干扰治疗反应，而绝种缺陷可能是PTSD发生的发病前危险因素。我们研究了暴露于严重的足底震颤以及情境提醒（SR）对海马CA1区和基底外侧杏仁核（BLA）的灭绝，可塑性和内源性大麻素（eCB）含量和活性的影响。我们还检查了使用脂肪酸酰胺水解酶（FAAH）抑制剂URB597增强灭绝前的eCB信号传导是否可以防止休克/ SRs引起的恐惧反应和可塑性影响。URB597全身给药（0。3毫克/千克）或在灭绝前局部进入CA1或BLA（0.1微克/侧）可减少恐惧恢复，这种效果在整个灭绝训练中持续存在，并且在自发恢复期间不会恢复。低剂量的CB1受体拮抗剂AM251（0.3 mg / kg腹膜内或0.01μg/ 0.5μl的CA1内或BLA内）阻断了这些作用，表明URB597的作用是CB1受体依赖性的。接触电击和提醒会诱发行为上的可塑性，对海马（受损）和BLA（增强）的长期增强（LTP）具有相反的作用。已发现URB597可防止海马和BLA-LTP中相反的休克/ SR诱导的可塑性。接触电击和提醒可能会导致内源性大麻素水平变化，从而影响恐惧电路功能。确实，暴露于休克和SR中会影响eCB含量：CA1中2-花生四烯酸甘油酯（2-AG）和N-花生四烯酸乙醇胺（AEA）含量增加，血清和BLA AEA含量降低，而休克暴露则增加CA1和BLA中的FAAH活性。灭绝前的FAAH抑制消除了恐惧，并调节了海马和杏仁核（与情感记忆有关的大脑区域）中的LTP。研究结果表明，在灭绝之前将eCB系统作为靶点可能有助于减轻恐惧记忆，并且这些影响可能涉及CA1和BLA的可塑性。灭绝前的FAAH抑制消除了恐惧，并调节了海马和杏仁核（与情感记忆有关的大脑区域）中的LTP。研究结果表明，在灭绝之前将eCB系统作为靶点可能有助于减轻恐惧记忆，并且这些影响可能涉及CA1和BLA的可塑性。灭绝前的FAAH抑制消除了恐惧，并调节了海马和杏仁核（与情感记忆有关的大脑区域）中的LTP。研究结果表明，在灭绝之前将eCB系统作为靶点可能有助于减轻恐惧记忆，并且这些影响可能涉及CA1和BLA的可塑性。