National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Mol Metab. 2022 Nov;65:101597. doi: 10.1016/j.molmet.2022.101597. Epub 2022 Sep 9.
Contextual drug-associated memory precipitates craving and relapse in substance users, and the risk of relapse is a major challenge in the treatment of substance use disorders. Thus, understanding the neurobiological underpinnings of how this association memory is formed and maintained will inform future advances in the treatment of drug addiction. Brain endocannabinoids (eCBs) signalling has been associated with drug-induced neuroadaptations, but the role of lipases that mediate small lipid ligand biosynthesis and metabolism in regulating drug-associated memory has not been examined. Here, we explored how manipulation of the lipase fatty acid amide hydrolase (FAAH), which is involved in mediating the level of the lipid ligand anandamide (AEA), affects cocaine-associated memory formation.
We applied behavioural, pharmacological and biochemical methods to detect cocaine-associated memory formation, eCBs in the dorsal dentate gyrus (dDG), and the activity of related enzymes. We further examined the roles of abnormal FAAH activity and AEA-CB1R signalling in the regulation of cocaine-associated memory formation and granule neuron dendritic structure alterations in the dDG through Western blotting, electron microscopy and immunofluorescence.
In the present study, we found that cocaine induced a decrease in the level of FAAH in the dDG and increased the level of AEA. A high level of AEA activated cannabinoid type 1 receptors (CB1Rs) and further triggered CB1R signalling activation and granule neuron dendritic remodelling, and these effects were reversed by blockade of CB1Rs in the brain. Furthermore, inhibition of FAAH in the dDG markedly increased AEA levels and promoted cocaine-associated memory formation through CB1R signalling activation.
Together, our findings demonstrate that the lipase FAAH influences CB1R signalling activation and granule neuron dendritic structure alteration in the dDG by regulating AEA levels and that AEA and AEA metabolism play a key role in cocaine-associated memory formation. Manipulation of AEA production may serve as a potential therapeutic strategy for drug addiction and relapse prevention.
语境药物相关记忆会引发物质使用者的渴望和复吸，而复吸的风险是物质使用障碍治疗的主要挑战。因此，了解这种关联记忆是如何形成和维持的神经生物学基础将为未来治疗药物成瘾提供信息。脑内大麻素（eCBs）信号与药物引起的神经适应性改变有关，但调节药物相关记忆的脂酶（介导小分子脂质配体生物合成和代谢）的作用尚未被研究。在这里，我们探讨了参与调节脂质配体大麻素（AEA）水平的脂肪酰胺水解酶（FAAH）的操纵如何影响可卡因相关记忆的形成。
我们应用行为学、药理学和生物化学方法来检测可卡因相关记忆的形成、背齿状回（dDG）中的 eCBs 以及相关酶的活性。我们进一步通过 Western blot、电子显微镜和免疫荧光检查了异常 FAAH 活性和 AEA-CB1R 信号在调节 dDG 中可卡因相关记忆形成和颗粒神经元树突结构改变中的作用。
在本研究中，我们发现可卡因诱导 dDG 中 FAAH 水平降低，AEA 水平升高。高水平的 AEA 激活大麻素 1 型受体（CB1Rs），并进一步触发 CB1R 信号激活和颗粒神经元树突重塑，而这些作用可通过脑内 CB1R 阻断来逆转。此外，dDG 中 FAAH 的抑制显著增加了 AEA 水平，并通过 CB1R 信号激活促进可卡因相关记忆的形成。
总之，我们的研究结果表明，脂肪酶 FAAH 通过调节 AEA 水平影响 dDG 中 CB1R 信号激活和颗粒神经元树突结构改变，AEA 和 AEA 代谢在可卡因相关记忆形成中起关键作用。AEA 产生的操纵可能是治疗药物成瘾和预防复吸的一种潜在治疗策略。
