Department of Pharmacy, Unit of Pharmacology and Toxicology and Center of Excellence for Biomedical Research, Università degli Studi di Genova, Genova, Italy.
BMC Neurosci. 2013 Jul 29;14:75. doi: 10.1186/1471-2202-14-75.
Growing compelling evidence from clinical and preclinical studies has demonstrated the primary role of alterations of glutamatergic transmission in cortical and limbic areas in the pathophysiology of mood disorders. Chronic antidepressants have been shown to dampen endogenous glutamate release from rat hippocampal synaptic terminals and to prevent the marked increase of glutamate overflow induced by acute behavioral stress in frontal/prefrontal cortex. Agomelatine, a new antidepressant endowed with MT1/MT2 agonist and 5-HT2C serotonergic antagonist properties, has shown efficacy at both preclinical and clinical levels.
Chronic treatment with agomelatine, or with the reference drug venlafaxine, induced a marked decrease of depolarization-evoked endogenous glutamate release from purified hippocampal synaptic terminals in superfusion. No changes were observed in GABA release. This effect was accompanied by reduced accumulation of SNARE protein complexes, the key molecular effector of vesicle docking, priming and fusion at presynaptic membranes.
Our data suggest that the novel antidepressant agomelatine share with other classes of antidepressants the ability to modulate glutamatergic transmission in hippocampus. Its action seems to be mediated by molecular mechanisms located on the presynaptic membrane and related with the size of the vesicle pool ready for release.
越来越多的临床前和临床研究证据表明，皮质和边缘区域谷氨酸能传递的改变在心境障碍的病理生理学中起主要作用。慢性抗抑郁药已被证明能抑制大鼠海马突触末梢内源性谷氨酸的释放，并能防止急性行为应激引起的前额/前额皮质谷氨酸溢出的显著增加。阿戈美拉汀是一种新型抗抑郁药，具有 MT1/MT2 激动剂和 5-HT2C 血清素拮抗剂的特性，在临床前和临床水平均显示出疗效。
阿戈美拉汀或参照药物文拉法辛的慢性治疗，在灌流中导致纯化的海马突触末梢去极化诱发的内源性谷氨酸释放明显减少。GABA 释放没有变化。这种效应伴随着 SNARE 蛋白复合物的积累减少，SNARE 蛋白复合物是囊泡停泊、启动和融合的关键分子效应器，位于突触前膜上。
我们的数据表明，新型抗抑郁药阿戈美拉汀与其他类别的抗抑郁药一样，具有调节海马谷氨酸能传递的能力。它的作用似乎是通过位于突触前膜上的分子机制介导的，与准备释放的囊泡池的大小有关。
