Department of Biology, Valdosta State University, Valdosta, GA, 31602, USA.
Psychopharmacology (Berl). 2012 Nov;224(2):231-40. doi: 10.1007/s00213-012-2743-8. Epub 2012 May 18.
Entrainment of circadian rhythms to the light-dark cycle is essential for restorative sleep, and abnormal sleep timing is implicated in central nervous system (CNS) disorders like depression, schizophrenia, and Alzheimer's disease. Many transmitters, including acetylcholine, that exerts its actions via muscarinic receptors modulate the suprachiasmatic nucleus, the master pacemaker.
Since positive allosteric modulators of muscarinic M(4) receptors are candidates for treatment of mood and cognitive deficits of CNS disorders, it is important to evaluate their circadian actions.
The effects of intraperitoneally applied muscarinic agents on circadian wheel-running rhythms were measured employing hamsters, a model organism for studying activity rhythms.
Systemic administration of the muscarinic receptor agonist oxotremorine (0.01-0.04 mg/kg) inhibited light-induced phase delays and advances of hamster circadian wheel-running rhythms. The M₄ positive allosteric modulator, LY2033298 (10-40 mg/kg), had no effect on light-induced phase shifts when administered alone, yet significantly enhanced (at 20 mg/kg) the inhibitory influence of oxotremorine on light-induced phase delays. In addition, the muscarinic receptor antagonist, scopolamine, which was without effect on light-induced phase shifts when administered alone (0.001-0.1 mg/kg), antagonized (at 0.1 mg/kg) the inhibitory effect of oxotremorine and LY2033298 on light-induced phase delays.
These results are the first to demonstrate that systemically applied muscarinic receptor agonists modulate circadian activity rhythms, and they also reveal a specific role for M₄ receptors. It will be of importance to evaluate circadian actions of psychotropic drugs acting via M₄ receptors, since they may display beneficial properties under pathological conditions.
将昼夜节律与光暗周期同步是恢复性睡眠的关键，而睡眠时间异常与中枢神经系统（CNS）疾病如抑郁症、精神分裂症和阿尔茨海默病有关。许多递质，包括通过毒蕈碱受体发挥作用的乙酰胆碱，调节视交叉上核，即主起搏器。
由于毒蕈碱 M（4）受体的正变构调节剂是治疗 CNS 疾病的情绪和认知缺陷的候选药物，因此评估其昼夜节律作用非常重要。
使用仓鼠作为研究活动节律的模型生物，测量腹腔内给予毒蕈碱药物对昼夜轮跑节律的影响。
系统给予毒蕈碱受体激动剂 oxotremorine（0.01-0.04 mg/kg）可抑制光诱导的仓鼠昼夜轮跑节律的相位延迟和提前。M₄ 正变构调节剂 LY2033298（10-40 mg/kg）单独给药时对光诱导的相移没有影响，但显着增强（20 mg/kg） oxotremorine 对光诱导的相延迟的抑制作用。此外，单独给予时对光诱导的相移没有影响的毒蕈碱受体拮抗剂东莨菪碱（0.001-0.1 mg/kg）拮抗 oxotremorine 和 LY2033298 对光诱导的相延迟的抑制作用。
这些结果首次证明系统给予毒蕈碱受体激动剂可调节昼夜活动节律，并且还揭示了 M₄ 受体的特定作用。评估通过 M₄ 受体发挥作用的精神药物的昼夜作用非常重要，因为它们在病理条件下可能具有有益的特性。
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