背景:尽管我们对抑郁症的病理生理学了解不足,越来越多的证据表明,谷氨酸和γ-氨基丁酸(GABA)信号在速效抗抑郁药(RAAD)作用背后的作用。GPR39是一种锌敏感受体,其激活导致小鼠长期的抗抑郁样反应。GPR39和锌都可以调节谷氨酸能和GABA能神经传递,然而,确切的分子机制仍然难以捉摸。在这项研究中,我们旨在研究谷氨酸能和GABA能系统激活在TC-G1008类抗抑郁作用中的作用,以及低锌饮食对这种作用的破坏.
方法:在我们研究的第一部分,我们研究了联合施用GPR39激动剂(TC-G1008)和谷氨酸能或GABA能系统的配体的作用,类似抗抑郁的反应。为了评估动物行为,我们在小鼠中使用了强迫游泳测试。在研究的第二部分,我们通过对参与谷氨酸能和GABA能神经传递的部分蛋白质进行Western印迹分析,评估了TC-G1008诱导的抗抑郁药样反应在膳食锌摄入量减少及其分子基础条件下的有效性.
结果:通过施用NMDA或黄质毒素阻断了TC-G1008诱导的作用。TC-G1008与麝香酚或SCH50911的联合给药显示出减少不动时间的趋势。缺锌饮食导致GluN1、PSD95和KCC2蛋白表达失调。
结论:我们的发现表明谷氨酸/GABA信号传导在TC-G1008的抗抑郁样作用中的重要作用,并暗示GPR39调节大脑中兴奋和抑制活性之间的平衡。因此,我们建议锌敏感受体被认为是开发新型抗抑郁药的一个有趣的新靶点。
BACKGROUND: Despite our poor understanding of the pathophysiology of depression, a growing body of evidence indicates the role of both glutamate and gamma-aminobutyric acid (GABA) signaling behind the effects of rapid-acting antidepressants (RAADs).
GPR39 is a zinc-sensing receptor whose activation leads to a prolonged antidepressant-like response in mice. Both
GPR39 and zinc can modulate glutamatergic and GABAergic neurotransmission, however, exact molecular mechanisms are still elusive. In this study, we aimed to research the role of glutamatergic and GABAergic system activation in TC-G 1008 antidepressant-like effects and the disruptions in this effect caused by a low-zinc diet.
METHODS: In the first part of our study, we investigated the role of joint administration of the
GPR39 agonist (TC-G 1008) and ligands of the glutamatergic or GABAergic systems, in antidepressant-like response. To evaluate animal behaviour we used the forced swim test in mice. In the second part of the study, we assessed the effectiveness of TC-G 1008-induced antidepressant-like response in conditions of decreased dietary zinc intake and its molecular underpinning by conducting a Western Blot analysis of selected proteins involved in glutamatergic and GABAergic neurotransmission.
RESULTS: The TC-G 1008-induced effect was blocked by the administration of NMDA or picrotoxin. The joint administration of TC-G 1008 along with muscimol or SCH50911 showed a trend toward decreased immobility time. Zinc-deficient diet resulted in dysregulation of GluN1, PSD95, and KCC2 protein expression.
CONCLUSIONS: Our findings indicate the important role of glutamate/GABA signaling in the antidepressant-like effect of TC-G 1008 and imply that
GPR39 regulates the balance between excitatory and inhibitory activity in the brain. Thus, we suggest the zinc-sensing receptor be considered an interesting new target for the development of novel antidepressants.