Abstract

There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics – psychedelic, anesthetic, and dissociative agents – as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNS’s resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research.

Graphical Abstract

中文翻译：

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缺失的部分？小胶质细胞在麻醉剂、氯胺酮和迷幻剂治疗作用中的突出作用

摘要

最近对有希望的、机械上新颖的心理治疗药物（致幻剂、麻醉剂和解离剂）的研究令人兴奋，因为它们在治疗中枢神经系统 (CNS) 疾病（例如情绪障碍和成瘾）方面表现出惊人的功效。然而，这些药物提供如此深远的心理益处的机制仍有待完全阐明。小胶质细胞是中枢神经系统的先天性免疫细胞，由于它们在调节神经可塑性和大脑炎症环境中的关键作用，正在成为精神疾病的细胞靶点。以下论文回顾了最近围绕这些神经药理学疗法及其已证实或假设的与小胶质细胞的相互作用的文献。通过研究迷幻剂（例如裸盖菇素和麦角酸二乙胺、氯胺酮和丙泊酚）的作用机制，我们证明了在围绕这些药物的许多新兴研究中，小胶质细胞的作用在很大程度上未被充分研究。其中，我们详细介绍了 sigma-1 受体、5-羟色胺能和 γ-氨基丁酸信号传导以及色氨酸代谢，这些药物通过这些途径调节小胶质细胞吞噬活性和炎症介质释放，从而诱导其治疗效果。当前的综述包括对小胶质细胞药理学领域未来方向的讨论，涵盖小胶质细胞和这些新型药物在衰老和年龄相关疾病、神经胶质细胞异质性和小胶质细胞研究中的最新方法的双向影响.

图形概要