背景:速效抗抑郁药(RAAD),包括解离性麻醉药,迷幻药,和移态药,通过据称调节神经可塑性来引发精神疾病的快速和持续的治疗改善,神经传递,和豁免权。这些结果可能是由,或导致,表观遗传过程的急性和/或持续夹带,重塑染色质结构并改变DNA可及性以调节基因表达。
方法:从这个角度来看,我们概述了已知的机制,知识差距,以及围绕RAAD表观遗传效应的未来方向,专注于压力反应性DNA和大脑区域的调节,以及与常规抗抑郁药的比较。
方法:初步相关证据表明,RAAD的给药伴随着表观遗传效应,这与常规抗抑郁药引起的效应相似。这些包括DNA甲基化的变化,组蛋白的翻译后修饰,和非编码RNA在涉及神经营养的应激反应染色质区域的差异调节,神经传递,和免疫调节,在应激反应的大脑区域。这些表观遗传变化是否对RAAD的治疗效果有因果关系,是其后果,或者是无关的,仍然未知。此外,潜在的细胞类型特异性和相关机制尚未完全阐明。候选机制包括神经元活性和5-羟色胺和原肌苷受体激酶B(TRKB)信号介导的表观遗传变化,与DNA的直接相互作用,组蛋白,或染色质重塑复合物。
结论:相关证据表明,RAAD诱导的表观遗传变化伴随治疗和副作用,虽然因果关系,机制,和细胞类型特异性仍然很大程度上未知。解决这些研究空白可能会导致新的基于神经表观遗传学的精确疗法的发展。
BACKGROUND: Rapid-acting antidepressants (RAADs), including dissociative anesthetics, psychedelics, and empathogens, elicit rapid and sustained therapeutic improvements in psychiatric disorders by purportedly modulating neuroplasticity, neurotransmission, and immunity. These outcomes may be mediated by, or result in, an acute and/or sustained entrainment of epigenetic processes, which remodel chromatin structure and alter DNA accessibility to regulate gene expression.
METHODS: In this perspective, we present an overview of the known mechanisms, knowledge gaps, and future directions surrounding the epigenetic effects of RAADs, with a focus on the regulation of stress-responsive DNA and brain regions, and on the comparison with conventional antidepressants.
METHODS: Preliminary correlative evidence indicates that administration of RAADs is accompanied by epigenetic effects which are similar to those elicited by conventional antidepressants. These include changes in DNA methylation, post-translational modifications of
histones, and differential regulation of non-coding RNAs in stress-responsive chromatin areas involved in neurotrophism, neurotransmission, and immunomodulation, in stress-responsive brain regions. Whether these epigenetic changes causally contribute to the therapeutic effects of RAADs, are a consequence thereof, or are unrelated, remains unknown. Moreover, the potential cell type-specificity and mechanisms involved are yet to be fully elucidated. Candidate mechanisms include neuronal activity- and serotonin and Tropomyosine Receptor Kinase B (TRKB) signaling-mediated epigenetic changes, and direct interaction with DNA,
histones, or chromatin remodeling complexes.
CONCLUSIONS: Correlative evidence suggests that epigenetic changes induced by RAADs accompany therapeutic and side effects, although causation, mechanisms, and cell type-specificity remain largely unknown. Addressing these research gaps may lead to the development of novel neuroepigenetics-based precision therapeutics.