Université Paris-Sud EA3544, Laboratoire Neuropharmacologie, Faculté de Pharmacie, Châtenay-Malabry, France.
Institut de Recherches Internationales Servier, Courbevoie, France.
Int J Neuropsychopharmacol. 2012 Apr;15(3):321-35. doi: 10.1017/S1461145711000356. Epub 2011 Apr 8.
Agomelatine (S20098) is a novel antidepressant drug with melatonergic agonist and 5-HT2C receptor antagonist properties, displaying antidepressant/anxiolytic-like properties in animal models and in humans. In a depression/anxiety-like mouse model in which the response of the HPA axis is blunted, we investigated whether agomelatine could reverse behavioural deficits related to depression/anxiety compared to the classical selective serotonin reuptake inhibitor, fluoxetine. Adult mice were treated for 8 wk with either vehicle or corticosterone (35 μg/ml.d) via drinking water. During the final 4 wk, animals were treated with vehicle, agomelatine (10 or 40 mg/kg i.p.) or fluoxetine (18 mg/kg i.p.) and tested in several behavioural paradigms and also evaluated for home-cage activity. Our results showed that the depressive/anxiety-like phenotype induced by corticosterone treatment is reversed by either chronic agomelatine or fluoxetine treatment. Moreover, agomelatine increased the dark/light ratio of home-cage activity in vehicle-treated mice and reversed the alterations in this ratio induced by chronic corticosterone, suggesting a normalization of disturbed circadian rhythms. Finally, we investigated the effects of this new antidepressant on neurogenesis. Agomelatine reversed the decreased cell proliferation in the whole hippocampus in corticosterone-treated mice and increased maturation of newborn neurons in both vehicle- and corticosterone-treated mice. Overall, the present study suggests that agomelatine, with its distinct mechanism of action based on the synergy between the melatonergic agonist and 5-HT2C antagonist properties, provides a distinct antidepressant/anxiolytic spectrum including circadian rhythm normalization.
阿戈美拉汀（S20098）是一种新型抗抑郁药，具有褪黑素激动剂和 5-HT2C 受体拮抗剂特性，在动物模型和人类中显示出抗抑郁/抗焦虑样特性。在一种 HPA 轴反应减弱的抑郁/焦虑样小鼠模型中，我们研究了与经典选择性 5-羟色胺再摄取抑制剂氟西汀相比，阿戈美拉汀是否可以逆转与抑郁/焦虑相关的行为缺陷。成年小鼠通过饮用水接受 8 周的 vehicle 或皮质酮（35 μg/ml.d）治疗。在最后 4 周，动物接受 vehicle、阿戈美拉汀（10 或 40 mg/kg，ip）或氟西汀（18 mg/kg，ip）治疗，并在几种行为范式中进行测试，还评估了其在笼内的活动。我们的结果表明，皮质酮处理诱导的抑郁/焦虑样表型可被慢性阿戈美拉汀或氟西汀治疗逆转。此外，阿戈美拉汀增加了 vehicle 处理小鼠的笼内活动的黑暗/光亮比值，并逆转了慢性皮质酮引起的这种比值的改变，表明昼夜节律紊乱得到了正常化。最后，我们研究了这种新型抗抑郁药对神经发生的影响。阿戈美拉汀逆转了皮质酮处理小鼠整个海马中细胞增殖的减少，并增加了 vehicle 和皮质酮处理小鼠中新神经元的成熟。总体而言，本研究表明，阿戈美拉汀具有独特的作用机制，基于褪黑素激动剂和 5-HT2C 拮抗剂特性的协同作用，提供了一种独特的抗抑郁/抗焦虑谱，包括昼夜节律正常化。
