Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Genetics. 2010 Nov;186(3):929-41. doi: 10.1534/genetics.110.118877. Epub 2010 Aug 25.
Fluoxetine is one of the most commonly prescribed medications for many behavioral and neurological disorders. Fluoxetine acts primarily as an inhibitor of the serotonin reuptake transporter (SERT) to block the removal of serotonin from the synaptic cleft, thereby enhancing serotonin signals. While the effects of fluoxetine on behavior are firmly established, debate is ongoing whether inhibition of serotonin reuptake is a sufficient explanation for its therapeutic action. Here, we provide evidence of two additional aspects of fluoxetine action through genetic analyses in Caenorhabditis elegans. We show that fluoxetine treatment and null mutation in the sole SERT gene mod-5 eliminate serotonin in specific neurons. These neurons do not synthesize serotonin but import extracellular serotonin via MOD-5/SERT. Furthermore, we show that fluoxetine acts independently of MOD-5/SERT to regulate discrete properties of acetylcholine (Ach), gamma-aminobutyric acid (GABA), and glutamate neurotransmission in the locomotory circuit. We identified that two G-protein-coupled 5-HT receptors, SER-7 and SER-5, antagonistically regulate the effects of fluoxetine and that fluoxetine binds to SER-7. Epistatic analyses suggest that SER-7 and SER-5 act upstream of AMPA receptor GLR-1 signaling. Our work provides genetic evidence that fluoxetine may influence neuronal functions and behavior by directly targeting serotonin receptors.
氟西汀是治疗许多行为和神经紊乱的最常用药物之一。氟西汀主要作为 5-羟色胺再摄取转运体（SERT）的抑制剂，以阻止 5-羟色胺从突触间隙中被清除，从而增强 5-羟色胺信号。虽然氟西汀对行为的影响已得到证实，但关于抑制 5-羟色胺再摄取是否足以解释其治疗作用仍存在争议。在这里，我们通过秀丽隐杆线虫的基因分析提供了氟西汀作用的另外两个方面的证据。我们表明，氟西汀处理和唯一的 SERT 基因 mod-5 的缺失突变会消除特定神经元中的 5-羟色胺。这些神经元本身不合成 5-羟色胺，但通过 MOD-5/SERT 从细胞外摄取 5-羟色胺。此外，我们还表明，氟西汀独立于 MOD-5/SERT 调节运动回路中乙酰胆碱（Ach）、γ-氨基丁酸（GABA）和谷氨酸神经递质的离散特性。我们发现两种 G 蛋白偶联的 5-HT 受体 SER-7 和 SER-5 拮抗地调节氟西汀的作用，并且氟西汀与 SER-7 结合。上位性分析表明，SER-7 和 SER-5 在 AMPA 受体 GLR-1 信号转导的上游发挥作用。我们的工作提供了遗传证据，表明氟西汀可能通过直接靶向 5-羟色胺受体来影响神经元功能和行为。
