Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.
Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.
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DOI：
10.3389/fnbeh.2020.620119
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发表时间：
2020
影响因子：
3
通讯作者：
Watson BO
中科院分区：
文献类型：
--
作者：
Fitzgerald PJ;Hale PJ;Ghimire A;Watson BO
当压力变成慢性时，它会引发持久的大脑和行为变化，包括重度抑郁症（MDD）。关于乙酰胆碱酯酶抑制剂（AChEI）是否具有抗抑郁作用，存在相互矛盾的证据。在最近的出版物中，我们在小鼠强迫游泳试验中证明了AChEI对抗抑郁症相关行为的作用具有很强的剂量依赖性：而AChEI多奈哌齐确实在高剂量下促进抑郁症样行为，在同一实验中，它在较低剂量下具有抗抑郁症样特性。因此，我们的数据表明多奈哌齐在抑郁相关行为中的Janus面剂量反应曲线。在这篇综述中，我们调查情绪相关的属性AChEIs更详细，专注于人类和啮齿动物的研究。事实上，虽然有许多研究显示AChEI具有促抑郁活性，这是该领域的一个主要概念，但在人类和啮齿动物中的各种其他研究显示了抗抑郁作用。我们的研究是第一个系统地改变剂量以包括非常低的浓度，同时测量行为影响的研究之一，这可能解释了该领域明显不同的发现。AChEI在啮齿动物中抗抑郁作用的可能性可能为新的抑郁症治疗提供希望。重要的是，MDD是一种与心理社会压力相关的疾病，在啮齿动物中，压力是研究抑郁机制的主要实验操作，因此未来的一个重要方向将是确定这些抑郁相关效应对压力敏感的程度。总之，在啮齿动物模型和人类受试者中，更好地了解低剂量乙酰胆碱酯酶抑制剂的潜在治疗情绪相关作用，应该是正在进行的转化研究的优先主题。
When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment. Our data therefore suggest a Janus-faced dose-response curve for donepezil in depression-related behavior. In this review, we investigate the mood-related properties of AChEIs in greater detail, focusing on both human and rodent studies. In fact, while there have been many studies showing pro-depressant activity by AChEIs and this is a major concept in the field, a variety of other studies in both humans and rodents show antidepressant effects. Our study was one of the first to systematically vary dose to include very low concentrations while measuring behavioral effects, potentially explaining the apparent disparate findings in the field. The possibility of antidepressant roles for AChEIs in rodents may provide hope for new depression treatments. Importantly, MDD is a psychosocial stress-linked disorder, and in rodents, stress is a major experimental manipulation for studying depression mechanisms, so an important future direction will be to determine the extent to which these depression-related effects are stress-sensitive. In sum, gaining a greater understanding of the potentially therapeutic mood-related effects of low dose AChEIs, both in rodent models and in human subjects, should be a prioritized topic in ongoing translational research.
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