Department of Psychology, University of Haifa, Haifa, 3498838, Israel.
Department of Pharmacology and Toxicology, Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, 53226, USA.
Neuropsychopharmacology. 2018 Sep;43(10):2017-2027. doi: 10.1038/s41386-018-0135-4. Epub 2018 Jun 27.
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.
创伤后应激障碍（PTSD）的特征是重新体验创伤事件，并且与恐惧反应的更快衰减有关。创伤相关线索的恐惧关联的衰减受损可能会干扰治疗反应，并且衰减不足可能是 PTSD 发展的潜在风险因素。我们研究了暴露于严重的足底电击后，情景提示（SRs）对海马 CA1 区和基底外侧杏仁核（BLA）的消退、可塑性和内源性大麻素（eCB）含量和活性的影响。我们还研究了在消退前使用脂肪酸酰胺水解酶（FAAH）抑制剂 URB597 增强 eCB 信号是否可以防止电击/SRs 对恐惧反应和可塑性的影响。在消退前全身给予 URB597（0.3mg/kg）或局部给予 CA1 或 BLA（0.1μg/侧）可降低恐惧检索，这种作用持续整个消退训练，并且在自发恢复期间没有恢复。低剂量的 CB1 受体拮抗剂 AM251（腹腔内 0.3mg/kg 或 CA1 内或 BLA 内 0.01μg/0.5μl）阻断了这些作用，表明 URB597 的作用是 CB1 受体依赖性的。暴露于电击和提示引起行为形质变化，对海马体（损伤）和 BLA（增强）的长时程增强（LTP）产生相反的影响。发现 URB597 可防止海马体和 BLA-LTP 中相反的电击/SR 诱导的形质变化。电击和提示的暴露可能导致内源性大麻素水平的变化，这可能会影响恐惧回路功能。事实上，电击和 SRs 的暴露会影响 eCB 含量：增加 CA1 中的 2-花生四烯酰甘油（2-AG）和 N-花生四烯酰乙醇胺（AEA）水平，降低血清和 BLA 的 AEA 水平，而电击暴露则增加 CA1 和 BLA 中的 FAAH 活性。在消退前抑制 FAAH 消除了恐惧，并调节了海马体和杏仁核中的 LTP，这些区域与情绪记忆有关。研究结果表明，在消退前靶向 eCB 系统可能有助于减轻恐惧记忆，并且这些作用可能涉及 CA1 和 BLA 中的形质变化。
