Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institute, 111 22 Stockholm, Sweden.
Int J Mol Sci. 2019 Aug 30;20(17):4247. doi: 10.3390/ijms20174247.
Major depressive disorder is one of the most common neuropsychiatric disorders worldwide. The treatment of choice that shows good efficacy in mood stabilization is based on selective serotonin reuptake inhibitors (SSRIs). Their primary mechanism of action is considered to be the increased synaptic concentration of serotonin through blockade of the serotonin transporter (SERT). In this study, we described an alternative mode of action of fluoxetine (FLX), which is a representative member of the SSRI class of antidepressants. We observed that FLX robustly decreases both glutamatergic and gamma-Aminobutyric acid (GABA)-ergic synaptic release in a SERT-independent manner. Moreover, we showed that this effect may stem from the ability of FLX to change the levels of main components of the SNARE (solubile -ethylmaleimide-sensitive factor attachment protein receptor) complex. Our data suggest that this downregulation of SNARE fusion machinery involves diminished activity of protein kinase C (PKC) due to FLX-induced blockade of P/Q type of voltage-gated calcium channels (VGCCs). Taken together, by virtue of its inhibition at SERT, fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.
重性抑郁障碍是全球最常见的神经精神疾病之一。在稳定情绪方面显示出良好疗效的首选治疗方法是基于选择性 5-羟色胺再摄取抑制剂（SSRIs）。其主要作用机制被认为是通过阻断 5-羟色胺转运体（SERT）增加突触间隙 5-羟色胺浓度。在这项研究中，我们描述了氟西汀（FLX）的一种替代作用模式，氟西汀是 SSRI 类抗抑郁药的代表性成员。我们观察到，FLX 以 SERT 非依赖性方式强烈降低谷氨酸能和γ-氨基丁酸（GABA）能突触释放。此外，我们表明，这种作用可能源于 FLX 改变 SNARE（可溶性 NSF 附着蛋白受体）复合物主要成分水平的能力。我们的数据表明，这种 SNARE 融合机制的下调涉及蛋白激酶 C（PKC）活性降低，这是由于 FLX 诱导的 P/Q 型电压门控钙通道（VGCC）阻断所致。总之，氟西汀通过抑制 SERT 增加细胞外 5-羟色胺水平；然而，与此同时，通过降低 SNARE 复合物的功能，这种抗抑郁药减少谷氨酸和 GABA 的释放。
