Instituto de Investigaciones Biosanitarias, Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Pozuelo de Alarcón, 28223 Madrid, Spain.
Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, PRBB, 08003 Barcelona, Spain.
Biomed Pharmacother. 2022 May;149:112925. doi: 10.1016/j.biopha.2022.112925. Epub 2022 Apr 9.
Anxiety and stress disorders are often characterized by an inability to extinguish learned fear responses. Orexins/hypocretins are involved in the modulation of aversive memories, and dysregulation of this system may contribute to the aetiology of anxiety disorders characterized by pathological fear. The mechanisms by which orexins regulate fear are unknown. Here we investigated the role of the endogenous cannabinoid system in the impaired fear extinction induced by orexin-A (OXA) in male mice. The selective inhibitor of 2-arachidonoylglycerol (2-AG) biosynthesis O7460 abolished the fear extinction deficits induced by OXA. Accordingly, increased 2-AG levels were observed in the amygdala and hippocampus of mice treated with OXA that do not extinguish fear, suggesting that high levels of this endocannabinoid are related to poor extinction. Impairment of fear extinction induced by OXA was associated with increased expression of CB2 cannabinoid receptor (CB2R) in microglial cells of the basolateral amygdala. Consistently, the intra-amygdala infusion of the CB2R antagonist AM630 completely blocked the impaired extinction promoted by OXA. Microglial and CB2R expression depletion in the amygdala with PLX5622 chow also prevented these extinction deficits. These results show that overactivation of the orexin system leads to impaired fear extinction through 2-AG and amygdalar CB2R. This novel mechanism could be of relevance for the development of novel potential approaches to treat diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder, panic anxiety and phobias.
焦虑和应激障碍的特征通常是无法消除习得的恐惧反应。食欲素/下丘脑分泌素参与厌恶记忆的调制，该系统的失调可能导致以病理性恐惧为特征的焦虑障碍的发病机制。食欲素调节恐惧的机制尚不清楚。在这里，我们研究了内源性大麻素系统在 OXA 诱导的雄性小鼠恐惧消退受损中的作用。2-花生四烯酸甘油（2-AG）生物合成的选择性抑制剂 O7460 消除了 OXA 诱导的恐惧消退缺陷。因此，在未消除恐惧的 OXA 处理的小鼠的杏仁核和海马体中观察到 2-AG 水平升高，表明这种内源性大麻素的高水平与不良的消退有关。OXA 诱导的恐惧消退受损与外侧杏仁核小胶质细胞中 CB2 大麻素受体（CB2R）表达增加有关。一致地，内侧杏仁核内注射 CB2R 拮抗剂 AM630 可完全阻断 OXA 促进的受损消退。PLX5622 饮食中杏仁核内的小胶质细胞和 CB2R 表达耗竭也可防止这些消退缺陷。这些结果表明，食欲素系统的过度激活通过 2-AG 和杏仁核 CB2R 导致恐惧消退受损。这种新的机制可能与开发治疗与恐惧不适当保留相关的疾病（如创伤后应激障碍、恐慌焦虑和恐惧症）的新的潜在方法有关。
