Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
Institute of Cell Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 64, 00143, Rome, Italy; European Brain Research Institute (EBRI), Rome, Italy.
Neuropharmacology. 2018 Aug;138:210-218. doi: 10.1016/j.neuropharm.2018.05.030. Epub 2018 May 26.
The endocannabinoid system is a key modulator of memory consolidation for aversive experiences. We recently found that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases anandamide levels by inhibiting its hydrolysis, facilitates memory consolidation through a concurrent activation of both cannabinoid receptor type 1 (CB1) and 2 (CB2). Here, we investigated the role played on memory consolidation by the other major endocannabinoid, 2-arachidonoylglycerol (2-AG). To this aim, we tested the effects of pharmacological inhibition of monoacylglycerol lipase (MAGL) through systemic administration of the MAGL inhibitor JZL184 to rats immediately after training of the inhibitory avoidance task. Pharmacological enhancement of 2-AG tone facilitated memory consolidation through activation of CB2 receptor signaling. Moreover, we found that increased 2-AG signaling prevented the activation of the mammalian target of rapamycin (mTOR) signaling pathway in the hippocampus through a CB2-dependent mechanism. Our results identify a fundamental role for 2-AG and CB2 receptors in the modulation of memory consolidation for aversive experiences.
内源性大麻素系统是调节厌恶体验记忆巩固的关键调节剂。我们最近发现，脂肪酸酰胺水解酶（FAAH）抑制剂 URB597 通过抑制其水解来增加花生四烯酸乙醇胺的水平，通过同时激活大麻素受体 1（CB1）和 2（CB2）促进记忆巩固。在这里，我们研究了另一种主要的内源性大麻素 2-花生四烯酸甘油（2-AG）在记忆巩固中所起的作用。为此，我们通过在抑制性回避任务训练后立即给大鼠系统给予单酰基甘油脂肪酶（MAGL）抑制剂 JZL184 来测试抑制 MAGL 对记忆巩固的影响。通过激活 CB2 受体信号，增加 2-AG 信号促进了记忆巩固。此外，我们发现增加的 2-AG 信号通过 CB2 依赖性机制防止了在海马中哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的激活。我们的研究结果确定了 2-AG 和 CB2 受体在调节厌恶体验记忆巩固中的基本作用。
