The endocannabinoid system as a target for novel anxiolytic drugs.
The endocannabinoid system as a target for novel anxiolytic drugs.
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DOI：
10.1016/j.neubiorev.2016.12.033
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发表时间：
2017-05
影响因子：
8.2
通讯作者：
Holmes A
中科院分区：
文献类型：
--
作者：
Patel S;Hill MN;Cheer JF;Wotjak CT;Holmes A
内源性大麻素（eCB）系统因其在各种行为和大脑功能中的作用而受到关注，并作为神经精神疾病状态的治疗靶点，包括焦虑症和其他由应激反应失调引起的疾病。在这篇小型综述中，我们重点介绍了eCB系统的组成部分，这些组成部分为新的抗焦虑药物提供了潜在的“可药物化”靶点，并强调了一些讨论较少的选择。我们讨论了通过脂肪酸酰胺水解酶（FAAH）和单酰基甘油脂肪酶（MAGL）干扰ecb降解，从而选择性地扩增ecb募集，如何与啮齿动物焦虑样行为的减少和人类焦虑症状的变化有关。我们还讨论了调节eCB降解的非规范途径，该途径涉及干扰环氧化酶-2 （COX-2）。接下来，我们讨论以不涉及大麻素受体亚型1 （CB1R）的方式靶向eCB受体信号的方法；通过靶向CB2R亚型和瞬时受体电位香草样蛋白1 (TRPV1)。最后，我们回顾了大麻二酚（CBD）的证据，虽然代表了一种不太具体的药理学方法，但可能是调节eCBs和相互作用的神经递质系统以减轻焦虑的另一种方法。综合起来，这些不同的方法为开发新的化合物提供了一系列可行的途径，这些化合物可能被证明对治疗创伤相关障碍和焦虑症有用。
The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential ‘druggable’ targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.