Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, 6439 Garners Ferry Rd, Columbia, SC 29208, USA.
Brain Res. 2012 Jul 23;1466:91-8. doi: 10.1016/j.brainres.2012.05.039. Epub 2012 May 27.
Agomelatine is a potent melatonergic (MT1 and MT2) receptor agonist and 5HT(2C) antagonist that is an effective antidepressant in animal models of depression and in patients suffering from depression. Our recent studies revealed that acute restraint stress increases extracellular levels of glutamate and GABA and that these increases in amino acid efflux are inhibited by some but not all antidepressants. In view of the increasing evidence supporting a role of amino acids in the pathology of depression, the current study examined whether acute stress-mediated changes in glutamate and GABA neurotransmission are modulated by agomelatine. In agreement with our previous work, acute stress increases extracellular glutamate levels in the basolateral nucleus of the amygdala (BLA). Similarly, acute stress increases glutamate efflux in the central nucleus of the amygdala (CeA). In the hippocampus, acute stress increases glutamate efflux and elicits an oscillatory pattern of GABA efflux. Agomelatine administration (40mg/kg ip) prior to acute stress inhibited stress-mediated increases in glutamate efflux in the hippocampus, BLA and CeA. These results demonstrate that acute agomelatine administration effectively inhibits acute stress-mediated changes in extracellular glutamate in the rat hippocampus and amygdala. While acute stress did not modulate GABA efflux in these regions, agomelatine treatment induced an overall reduction of GABA levels in the hippocampus. These data suggest that agomelatine modulates amino acid efflux in limbic structures implicated in major depressive disorder.
阿戈美拉汀是一种有效的抗抑郁药，具有很强的褪黑素能（MT1 和 MT2）受体激动剂和 5HT（2C）拮抗剂作用，在抑郁症动物模型和抑郁症患者中都有疗效。我们最近的研究表明，急性束缚应激会增加谷氨酸和 GABA 的细胞外水平，而这些氨基酸外排的增加被一些而不是所有的抗抑郁药所抑制。鉴于越来越多的证据支持氨基酸在抑郁症发病机制中的作用，本研究探讨了阿戈美拉汀是否调节急性应激介导的谷氨酸和 GABA 神经传递的变化。与我们之前的工作一致，急性应激会增加杏仁核基底外侧核（BLA）中的细胞外谷氨酸水平。同样，急性应激会增加杏仁核中央核（CeA）中的谷氨酸外排。在海马体中，急性应激会增加谷氨酸外排并引起 GABA 外排的振荡模式。急性应激前给予阿戈美拉汀（40mg/kg ip）可抑制应激介导的海马体、BLA 和 CeA 中谷氨酸外排的增加。这些结果表明，急性阿戈美拉汀给药可有效抑制大鼠海马体和杏仁核中急性应激介导的细胞外谷氨酸变化。虽然急性应激没有调节这些区域的 GABA 外排，但阿戈美拉汀治疗诱导了海马体中 GABA 水平的整体降低。这些数据表明，阿戈美拉汀调节与重度抑郁症相关的边缘结构中的氨基酸外排。
