Fluoxetine (LY-110140)

Fluoxetine (LY-110140) is an orally active, selective serotonin reuptake inhibitor (SSRI) commonly used to treat a variety of psychiatric disorders such as depression, obsessive-compulsive disorder, and panic disorder. Fluoxetine is a potent inhibitor of the saturable [3H]-5-HT (serotonin) uptake process in rat and human platelets, with IC₅₀ values of 0.10 and 0.05 μM, respectively^[1]. It exerts its antidepressant effects by specifically inhibiting the reuptake of serotonin (5-HT) in the central nervous system, thereby increasing the concentration of 5-HT in the brain.

In vitro, Fluoxetine (LY-110140) inhibits the K⁺ currents in OK cells in a concentration-dependent manner, with an EC₅₀ of 107 (84.8; 129.5) μM^[2]. Fluoxetine (LY-110140) (5 mg/kg; for 21 days) increases the number of newborn cells in the dentate gyrus of the hippocampus in adult rats, as well as the number of proliferating cells in the prefrontal cortex^[3].

In vivo, subchronic study of Fluoxetine (LY-110140) (10 mg/kg/day, orally) in adult male Wistar rats for 15 days significantly reduced urinary K⁺ excretion, indicating that fluoxetine has an inhibitory effect on renal epithelial K⁺ channels^[2]. After Fluoxetine (LY-110140) treatment, the observed delay in escape latency in adult male Sprague-Dawley rats was reversed^[4]. Furthermore, in SD rats, the combination of Fluoxetine (LY-110140) and olanzapine produced robust, sustained increases in extracellular levels of dopamine and norepinephrine, exceeding the baseline by 361% and 272%, respectively, an effect significantly greater than that of either drug used alone^[5].

References:

[1] David T. Wong, Kenneth W. Perry, Frank P. Bymaster, et al. The Discovery of Fluoxetine Hydrochloride (Prozac)[J]. Nature Reviews Drug Discovery volume 4, pages764–774 (2005).

[2] Vieira-Coelho M A ,Fátima. Martel. Inhibition of kidney potassium channels by fluoxetine: In vivo and in vitro studies[J].Fundamental & clinical pharmacology, 2022.

[3] Kodama M, et al. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry. 2004 Oct 15;56(8):570-80.

[4] Malberg JE, et al. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology. 2003 Sep;28(9):1562-71.

[5] Zhang W, et al. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology. 2000 Sep;23(3):250-62. 

氟西汀Fluoxetine (LY-110140)是一种具有口服活性的选择性5-羟色胺再摄取抑制剂（SSRI），常用于治疗抑郁症、强迫症、恐慌症等多种精神疾病。氟西汀是大鼠和人血小板中饱和[3H]-5-HT摄取过程的强效抑制剂，IC₅₀值分别为0.10和0.05 μM ^[1]。它通过特异性抑制中枢神经系统中的5-羟色胺（5-HT）再摄取，增加大脑中5-HT的浓度，从而发挥抗抑郁作用。

在体外，氟西汀对OK细胞中的K⁺电流产生浓度依赖性抑制，EC₅₀为107 (84.8; 129.5)μM^[2]。氟西汀（5 mg/kg; 21 days）增加成年大鼠的海马的齿状回的新生细胞的数量，也增加了前度皮质的增殖细胞的数目^[3]。

在体内，氟西汀（10 mg/kg/d/，p.o.）对雄性成年Wistar大鼠进行亚慢性研究15天，可显著降低尿K⁺排泄，说明氟西汀对肾上皮K⁺通道具有抑制作用^[2]。氟西汀治疗后，逆转了成年雄性Sprague-Dawley大鼠中观察到的逃避潜伏延迟问题^[4]。此外，在SD大鼠中，氟西汀和奥氮平联用产生稳健持续的细胞外多巴胺水平和去甲肾上腺素的增加，超过基准达361％和272％，效果显著大于两种药物单独使用^[5]。