The allosteric citalopram binding site differentially interferes with neuronal firing rate and SERT trafficking in serotonergic neurons

• Verfasst von: Matthäus, Friederike [VerfasserIn]
• Verfasst von: Schloss, Patrick [VerfasserIn]
• Titel: The allosteric citalopram binding site differentially interferes with neuronal firing rate and SERT trafficking in serotonergic neurons
• Verf.angabe: Friederike Matthäus, Nasser Haddjeri, Connie Sánchez, Yasmina Martí, Senda Bahri, Renaud Rovera, Patrick Schloss, Thorsten Lau
• E-Jahr: 2016
• Jahr: November 2016
• Umfang: 12 S.
• Fussnoten: Gesehen am 12.06.2019 ; Available online 21 September 2016
• Titel Quelle: Enthalten in: European neuropsychopharmacology
• Ort Quelle: Amsterdam : Elsevier, 1990
• Jahr Quelle: 2016
• Band/Heft Quelle: 26(2016), 11, Seite 1806-1817
• ISSN Quelle: 1873-7862
• DOI: doi:10.1016/j.euroneuro.2016.09.001
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Antidepressant treatment
• Sach-SW: Neuronal firing rate
• Sach-SW: Serotonergic neurons
• Sach-SW: SERT
• Sach-SW: Stem cells
• K10plus-PPN: 1667318373

Abstract

Citalopram is a clinically applied selective serotonin re-uptake inhibitor for antidepressant pharmacotherapy. It consists of two enantiomers, S-citalopram (escitalopram) and R-citalopram, of which escitalopram exerts the antidepressant therapeutic effect and has been shown to be one of the most efficient antidepressants, while R-citalopram antagonizes escitalopram via an unknown molecular mechanism that may depend on binding to a low-affinity allosteric binding site of the serotonin transporter. However, the precise mechanism of antidepressant regulation of the serotonin transporter by citalopram enantiomers still remains elusive. Here we investigate escitalopram׳s acute effect on (1) serotonergic neuronal firing in transgenic mice that express the human serotonin transporter without and with a mutation that disables the allosteric binding site, and (2) regulation of the serotonin transporter׳s cell surface localization in stem cell-derived serotonergic neurons. Our results demonstrate that escitalopram inhibited neuronal firing less potently in the mouse line featuring a mutation that abolishes the function of the allosteric binding site and induced serotonin transporter internalization independently of the allosteric binding site mechanism. Furthermore, citalopram enantiomers dose-dependently induced serotonin transporter internalization. In conclusion, this study provides new insight into antidepressant effects exerted by citalopram enantiomers in presence and absence of a functional allosteric binding site.