Multiple cholinesterase inhibitors have antidepressant-like properties in the mouse forced swim test.
Multiple cholinesterase inhibitors have antidepressant-like properties in the mouse forced swim test.
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DOI：
10.1016/j.bbr.2021.113323
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发表时间：
2021-07-09
影响因子：
2.7
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
改善重度抑郁障碍（MDD）患者的药物治疗具有很高的临床意义。这种神经精神疾病继续在世界范围内引起显著的发病率和死亡率，其中现有的药物治疗，如选择性血清素再摄取抑制剂，往往疗效有限。在最近发表的一篇文章中，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样作用。这些数据补充了关于啮齿动物和人类受试者的有限文献，这些文献表明AChEIs具有抗抑郁特性，但增加了新的发现，即多奈哌齐仅在较低剂量（0.02,0.2 mg/kg）下显示出类似抗抑郁的特性。在高剂量（2.0 mg/kg）下，多奈哌齐倾向于促进抑郁样行为，提示FST固定的u型剂量-反应曲线。在这里，我们研究了另外三种具有不同分子结构的乙酰胆碱抑制剂的作用：加兰他明、毒豆碱和利瓦斯汀，以测试它们是否也在FST中表现出类似抗抑郁药的作用。我们发现这些药物在低剂量而不是高剂量下确实表现出治疗样的效果，尽管在较低剂量下对毒豆碱。此外，我们发现它们的抗抑郁样作用不是由广泛性多动介导的，也不伴有焦虑样性质。这些数据进一步支持了乙酰胆碱与C57BL/6J小鼠FST中不动性呈u型剂量-反应关系的假设，并为更彻底地研究可逆性乙酰胆碱类药物是否可以重新用于治疗人类重度抑郁症提供了理论依据。
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.
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影响因子：
2.7
作者：
Giustino TF;Fitzgerald PJ;Maren S
通讯作者：
Maren S
影响因子：
3.4
作者：
Mineur YS;Bentham MP;Zhou WL;Plantenga ME;McKee SA;Picciotto MR
通讯作者：
Picciotto MR
影响因子：
3.6
作者：
Groft, Miranda L.;Normann, Marigny C.;McLaughlin, Peter J.
通讯作者：
McLaughlin, Peter J.
影响因子：
8.2
作者：
Liang, Yan-qi;Tang, Xi-can
通讯作者：
Tang, Xi-can
影响因子：
3
作者：
Giustino TF;Maren S
通讯作者：
Maren S