The allosteric citalopram binding site differentially interferes with neuronal firing rate and SERT trafficking in serotonergic neurons.
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.
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Department Psychiatry and Psychotherapy, Biochemical Laboratory, Mannheim, Germany.
Friederike
F
Matthäus
Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.
Nasser
N
Haddjeri
Sourcing and Scientific Excellence at Lundbeck Research USA, Inc., Paramus, NJ, USA.
Connie
C
Sánchez
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Department Psychiatry and Psychotherapy, Biochemical Laboratory, Mannheim, Germany.
Yasmina
Y
Martí
Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.
Senda
S
Bahri
Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France.
Renaud
R
Rovera
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Department Psychiatry and Psychotherapy, Biochemical Laboratory, Mannheim, Germany.
Patrick
P
Schloss
Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Department Psychiatry and Psychotherapy, Biochemical Laboratory, Mannheim, Germany. Electronic address: Thorsten.lau@zi-mannheim.de.
Thorsten
T
Lau
D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects; D015283:Citalopram / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects; D059326:Serotonergic Neurons / Q000187:drug effects*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism
D000928:Antidepressive Agents; D011956:Receptors, Cell Surface; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D015283:Citalopram
Antidepressant treatment; Neuronal firing rate; SERT; Serotonergic neurons; Stem cells