Department of Molecular Neurobiology, University of Groningen, The Netherlands.
CNS Neurosci Ther. 2010 Aug;16(4):195-207. doi: 10.1111/j.1755-5949.2009.00125.x. Epub 2010 Mar 11.
Agomelatine is a novel antidepressant which acts as a melatonergic (MT1/MT2) receptor agonist and serotonergic (5-HT2C) receptor antagonist. The antidepressant properties of agomelatine have been demonstrated in animal models as well as in clinical studies. Several preclinical studies reported agomelatine-induced effects on brain plasticity, mainly under basal conditions in healthy animals. Yet, it is important to unravel agomelatine-mediated changes in the brain affected by psychopathology or exposed to conditions that might predispose to mood disorders. Since stress is implicated in the etiology of depression, it is valid to investigate antidepressant-induced effects in animals subjected to chronic stress. In this context, we sought to determine changes in the brain after agomelatine treatment in chronically stressed rats. Adult male rats were subjected to footshock stress and agomelatine treatment for 21 consecutive days. Rats exposed to footshock showed a robust increase in adrenocorticotropic hormone (ACTH) and corticosterone. Chronic agomelatine treatment did not markedly influence this HPA-axis response. Whereas chronic exposure to daily footshock stress reduced c-Fos expression in the hippocampal dentate gyrus, agomelatine treatment reversed this effect and normalized neuronal activity to basal levels. Moreover, chronic agomelatine administration was associated with enhanced hippocampal cell proliferation and survival in stressed but not in control rats. Furthermore, agomelatine reversed the stress-induced decrease in doublecortin expression in the dentate gyrus. Taken together, these data show a beneficial action of agomelatine in the stress-compromised brain, where it restores stress-affected hippocampal neuronal activity and promotes adult hippocampal neurogenesis.
阿戈美拉汀是一种新型抗抑郁药，作为一种褪黑素能（MT1/MT2）受体激动剂和血清素（5-HT2C）受体拮抗剂。阿戈美拉汀的抗抑郁特性已在动物模型和临床研究中得到证实。几项临床前研究报告了阿戈美拉汀对大脑可塑性的影响，主要是在健康动物的基础条件下。然而，重要的是要揭示阿戈美拉汀在受精神病理学影响或暴露于可能导致情绪障碍的条件下对大脑的介导变化。由于应激与抑郁的病因有关，因此在慢性应激的动物中研究抗抑郁药的诱导作用是合理的。在这种情况下，我们试图确定慢性应激大鼠接受阿戈美拉汀治疗后的大脑变化。成年雄性大鼠接受足底电击应激和阿戈美拉汀治疗 21 天。暴露于足底电击的大鼠表现出促肾上腺皮质激素（ACTH）和皮质酮的显著增加。慢性阿戈美拉汀治疗并没有显著影响这种 HPA 轴反应。虽然慢性暴露于每日足底电击应激会降低海马齿状回中的 c-Fos 表达，但阿戈美拉汀治疗逆转了这种效应，并使神经元活性恢复到基础水平。此外，慢性阿戈美拉汀给药与应激大鼠海马中的细胞增殖和存活增加有关，但在对照大鼠中没有。此外，阿戈美拉汀逆转了应激引起的齿状回中双皮质素表达的减少。总之，这些数据显示阿戈美拉汀在应激受损的大脑中具有有益的作用，它恢复了受应激影响的海马神经元活性，并促进了成年海马神经发生。
