University of Michigan, Department of Psychiatry, Ann Arbor, MI, 48109, United States.
University of Michigan, Department of Psychiatry, Ann Arbor, MI, 48109, United States.
Behav Brain Res. 2021 Jul 9;409:113323. doi: 10.1016/j.bbr.2021.113323. Epub 2021 Apr 25.
There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST). Those data added to a limited literature in rodents and human subjects which suggests AChEIs have antidepressant properties, but added the novel finding that donepezil only showed antidepressant-like properties at lower doses (0.02, 0.2 mg/kg). At a high dose (2.0 mg/kg), donepezil tended to promote depression-like behavior, suggesting a u-shaped dose-response curve for FST immobility. Here we investigate the effects of three other AChEIs with varying molecular structures: galantamine, physostigmine, and rivastigmine, to test whether they also exhibit antidepressant-like effects in the FST. We find that these drugs do exhibit therapeutic-like effects at low but not high doses, albeit at lower doses for physostigmine. Further, we find that their antidepressant-like effects are not mediated by generalized hyperactivity in the novel open field test, and are also not accompanied by anxiolytic-like properties. These data further support the hypothesis that acetylcholine has a u-shaped dose-response relationship with immobility in the C57BL/6J mouse FST, and provide a rationale for more thoroughly investigating whether reversible AChEIs as a class can be repurposed for the treatment of MDD in human subjects.
临床上人们对改善重度抑郁症（MDD）患者的药物治疗非常感兴趣。这种神经精神疾病仍然在全世界范围内导致很高的发病率和死亡率，而现有的药物治疗，如选择性 5-羟色胺再摄取抑制剂，往往疗效有限。在最近的一篇出版物中，我们在 C57BL/6J 小鼠强迫游泳试验（FST）中证明了乙酰胆碱酯酶抑制剂（AChEI）多奈哌齐具有抗抑郁作用。这些数据增加了在啮齿动物和人类受试者中有限的文献，表明 AChEIs 具有抗抑郁特性，但增加了一个新的发现，即多奈哌齐仅在较低剂量（0.02、0.2mg/kg）下显示出抗抑郁样特性。在高剂量（2.0mg/kg）时，多奈哌齐倾向于促进抑郁样行为，表明 FST 不动性呈 U 形剂量反应曲线。在这里，我们研究了三种具有不同分子结构的其他 AChEIs 的作用：加兰他敏、石杉碱甲和利伐斯的明，以测试它们是否也在 FST 中表现出抗抑郁样作用。我们发现，这些药物在低剂量但不在高剂量下表现出治疗样作用，尽管石杉碱甲的剂量较低。此外，我们发现它们的抗抑郁样作用不是通过新的开阔场试验中的一般过度活跃介导的，也没有伴随焦虑样特性。这些数据进一步支持了乙酰胆碱在 C57BL/6J 小鼠 FST 中与不动性呈 U 形剂量反应关系的假设，并为更彻底地研究作为一类的可逆性 AChEIs 是否可以重新用于人类 MDD 的治疗提供了依据。
