背景:胆碱能系统越来越多地与抑郁症等情绪障碍的病理生理学联系在一起,与烟碱和/或毒蕈碱受体的潜在参与。常规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,东pol碱,非选择性毒蕈碱乙酰胆碱受体拮抗剂,可以诱导有效和快速的抗抑郁作用,只需要几天的治疗。这项研究旨在检查抑郁症的不可预测的慢性轻度应激(UCMS)模型是否适合再现上述东pol碱抗抑郁活性模式。
方法:使用飞溅试验评估快速和持续的抗抑郁药样作用,蔗糖偏好测试(SPT),尾部悬挂试验(TST),和在经历UCMS程序的动物和应激初治C57BL/6J小鼠中的强迫游泳试验(FST)。蛋白质印迹法用于测量原肌球蛋白受体激酶B(TrkB),哺乳动物雷帕霉素靶蛋白(mTOR),真核延伸因子(eEF2)和突触后密度蛋白95(PSD95)水平。
结果:东莨菪碱仅在亚慢性,但不是单身,在C57BL/6J小鼠抑郁的UCMS模型中施用而不影响运动活动。具体来说,东莨菪碱以0.3mg/kg的剂量连续4天显着逆转UCMS诱导的抑郁样行为,比如冷漠,快感缺失,和行为绝望,而东莨菪碱,给予相同的剂量,但只有一次,没有缓解上述症状。东莨菪碱治疗伴随着eEF2蛋白去磷酸化及其随后在前额叶皮质(PFC)中的重新激活。
结论:需要亚慢性给予东莨菪碱以改善UCMS诱导的抑郁样行为。东pol碱作用的建议机制涵盖PFC中的eEF2蛋白活性。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.