Tags

Type your tag names separated by a space and hit enter

Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies.
Int J Neuropsychopharmacol. 2007 Feb; 10(1):31-40.IJ

Abstract

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.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16448580

Citation

Mansari, Mostafa El, et al. "Allosteric Modulation of the Effect of Escitalopram, Paroxetine and Fluoxetine: In-vitro and In-vivo Studies." The International Journal of Neuropsychopharmacology, vol. 10, no. 1, 2007, pp. 31-40.
Mansari ME, Wiborg O, Mnie-Filali O, et al. Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. Int J Neuropsychopharmacol. 2007;10(1):31-40.
Mansari, M. E., Wiborg, O., Mnie-Filali, O., Benturquia, N., Sánchez, C., & Haddjeri, N. (2007). Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. The International Journal of Neuropsychopharmacology, 10(1), 31-40.
Mansari ME, et al. Allosteric Modulation of the Effect of Escitalopram, Paroxetine and Fluoxetine: In-vitro and In-vivo Studies. Int J Neuropsychopharmacol. 2007;10(1):31-40. PubMed PMID: 16448580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Allosteric modulation of the effect of escitalopram, paroxetine and fluoxetine: in-vitro and in-vivo studies. AU - Mansari,Mostafa El, AU - Wiborg,Ove, AU - Mnie-Filali,Ouissame, AU - Benturquia,Nadia, AU - Sánchez,Connie, AU - Haddjeri,Nasser, Y1 - 2006/02/01/ PY - 2005/07/14/received PY - 2005/11/15/revised PY - 2005/11/19/accepted PY - 2006/2/2/pubmed PY - 2007/3/31/medline PY - 2006/2/2/entrez SP - 31 EP - 40 JF - The international journal of neuropsychopharmacology JO - Int J Neuropsychopharmacol VL - 10 IS - 1 N2 - 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. SN - 1461-1457 UR - https://www.unboundmedicine.com/medline/citation/16448580/Allosteric_modulation_of_the_effect_of_escitalopram_paroxetine_and_fluoxetine:_in_vitro_and_in_vivo_studies_ L2 - https://academic.oup.com/ijnp/article-lookup/doi/10.1017/S1461145705006462 DB - PRIME DP - Unbound Medicine ER -