Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, Kraków, 31-343, Poland.
Pharmacol Rep. 2024 Oct;76(5):1001-1011. doi: 10.1007/s43440-024-00630-4. Epub 2024 Jul 23.
The cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns.
Rapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels.
Scopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC).
Subchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.
胆碱能系统与抑郁症等心境障碍的病理生理学越来越相关，其中可能涉及烟碱型和/或毒蕈碱型受体。传统的抗抑郁药通常需要数周的每日给药才能达到完全的抗抑郁反应。相比之下，临床研究表明，非选择性毒蕈碱乙酰胆碱受体拮抗剂东莨菪碱可诱导强效且快速的抗抑郁作用，仅需几天的治疗。本研究旨在检查不可预测的慢性轻度应激（UCMS）抑郁模型是否适合重现上述东莨菪碱抗抑郁作用模式。
通过溅水试验、蔗糖偏好试验（SPT）、悬尾试验（TST）和强迫游泳试验（FST）评估 UCMS 处理和应激-naive C57BL/6J 小鼠中的快速和持续抗抑郁样效应。Western Blotting 用于测量原肌球蛋白受体激酶 B（TrkB）、雷帕霉素靶蛋白（mTOR）、真核延伸因子（eEF2）和突触后密度蛋白 95（PSD95）水平。
东莨菪碱仅在慢性而非单次给药后，以剂量依赖性方式诱导 UCMS 抑郁模型中的抗抑郁样效应，而不影响运动活动。具体而言，东莨菪碱以 0.3mg/kg 的剂量连续给药 4 天可显著逆转 UCMS 诱导的抑郁样行为，如冷漠、快感缺失和行为绝望，而相同剂量但仅单次给药则不能缓解上述症状。东莨菪碱治疗伴有前额叶皮质（PFC）中 eEF2 蛋白去磷酸化及其随后的再激活。
需要亚慢性给予东莨菪碱以改善 UCMS 诱导的抑郁样行为。东莨菪碱作用的机制涉及 PFC 中的 eEF2 蛋白活性。
