Mansari Mostafa El, Wiborg Ove, Mnie-Filali Ouissame, Benturquia Nadia, Sánchez Connie, Haddjeri Nasser
Laboratory of Neuropharmacology and Neurochemistry, Faculty of Pharmacy, University of Claude Bernard Lyon I, INSERM EA-512, Lyon, France, and Department of Biological Psychiatry, Aarhus Psychiatric University Hospital, Risskov, Denmark.
Int J Neuropsychopharmacol. 2007 Feb;10(1):31-40. doi: 10.1017/S1461145705006462. Epub 2006 Feb 1.
Clinical and preclinical studies have shown that the effect of citalopram on serotonin (5-HT) reuptake inhibition and its antidepressant activity resides in the S-enantiomer. In addition, using a variety of in-vivo and in-vitro paradigms, it was shown that R-citalopram counteracts the effect of escitalopram. This effect was suggested to occur via an allosteric modulation at the level of the 5-HT transporter. Using in-vitro binding assays at membranes from COS-1 cells expressing the human 5-HT transporter (hSERT) and in-vivo electrophysiological and microdialysis techniques in rats, the present study was directed at determining whether R-citalopram modifies the action of selective serotonin reuptake inhibitors (SSRIs) known to act on allosteric sites namely escitalopram, and to a lesser extent paroxetine, compared to fluoxetine, which has no affinity for these sites. In-vitro binding studies showed that R-citalopram attenuated the association rates of escitalopram and paroxetine to the 5-HT transporter, but had no effect on the association rates of fluoxetine, venlafaxine or sertraline. In the rat dorsal raphe nucleus, R-citalopram (250 microg/kg i.v.) blocked the suppressant effect on neuronal firing activity of both escitalopram (100 microg/kg i.v.) and paroxetine (500 microg/kg i.v.), but not fluoxetine (10 mg/kg i.v.). Interestingly, administration of R-citalopram (8 mg/kg i.p.) attenuated the increase of extracellular levels of 5-HT ([5-HT]ext) in the ventral hippocampus induced by both escitalopram (0.28 microM) and paroxetine (0.75 microM), but not fluoxetine (10 microM). In conclusion, the present in-vitro and in-vivo studies show that R-citalopram counteracts the activity of escitalopram and paroxetine, but not fluoxetine, by acting at the allosteric binding site of the 5-HT transporter, either located in the dorsal raphe nucleus or post-synaptically in the ventral hippocampus. This conclusion is strengthened by the observation that the inhibitory effect of fluoxetine, which has no stabilizing effect on the radioligand/hSERT complex, was not blocked by co-administration of R-citalopram.
临床和临床前研究表明，西酞普兰对5-羟色胺（5-HT）再摄取的抑制作用及其抗抑郁活性存在于S-对映体中。此外，通过多种体内和体外实验范式表明，R-西酞普兰可抵消艾司西酞普兰的作用。提示该作用是通过5-HT转运体水平的变构调节发生的。本研究利用在表达人5-HT转运体（hSERT）的COS-1细胞膜上进行的体外结合试验以及大鼠体内电生理和微透析技术，旨在确定与对这些位点无亲和力的氟西汀相比，R-西酞普兰是否会改变已知作用于变构位点的选择性5-羟色胺再摄取抑制剂（SSRI）即艾司西酞普兰的作用，对帕罗西汀的作用程度较小。体外结合研究表明，R-西酞普兰减弱了艾司西酞普兰和帕罗西汀与5-HT转运体的结合速率，但对氟西汀、文拉法辛或舍曲林的结合速率没有影响。在大鼠中缝背核，R-西酞普兰（静脉注射250μg/kg）可阻断艾司西酞普兰（静脉注射100μg/kg）和帕罗西汀（静脉注射500μg/kg）对神经元放电活动的抑制作用，但不能阻断氟西汀（静脉注射10mg/kg）的作用。有趣的是，腹腔注射R-西酞普兰（8mg/kg）可减弱由艾司西酞普兰（0.28μM）和帕罗西汀（0.75μM）诱导的腹侧海马中细胞外5-HT水平（[5-HT]ext）的升高，但不能减弱氟西汀（10μM）诱导的升高。总之，目前的体内和体外研究表明，R-西酞普兰通过作用于位于中缝背核或腹侧海马突触后的5-HT转运体的变构结合位点，抵消了艾司西酞普兰和帕罗西汀的活性，但不能抵消氟西汀的活性。氟西汀对放射性配体/hSERT复合物没有稳定作用，其抑制作用不会因联合给予R-西酞普兰而被阻断，这一观察结果进一步支持了该结论。
