title: The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse.
abstract: BACKGROUND
  Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, there by curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence anti-depressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram's inhibition here of.
  
  
  OBJECTIVE
  Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram.
  
  
  METHODS
  Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying).
  
  
  RESULTS
  We generated mice expressing either the wild-type human SERT (hSERT(WT)) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERT(ALI/VFL+SI/TT)). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and tended to be enhanced by R-citalopram co-administration.
  
  
  CONCLUSIONS
  We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, PO Box 3287, Durham, NC, 27710, USA.
authors.forename: Jacob P R
authors.initials: JP
authors.lastname: Jacobsen
authors.forename: Per
authors.initials: P
authors.lastname: Plenge
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sachs
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
authors.forename: Manuel
authors.initials: M
authors.lastname: Cajina
authors.forename: Yunzhi
authors.initials: Y
authors.lastname: Du
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.forename: Meghan L
authors.initials: ML
authors.lastname: Rudder
authors.forename: Prachiti
authors.initials: P
authors.lastname: Dalvi
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Robinson
authors.forename: Sharon P
authors.initials: SP
authors.lastname: O'Neill
authors.forename: King S
authors.initials: KS
authors.lastname: Khoo
authors.forename: Connie Sanchez
authors.initials: CS
authors.lastname: Morillo
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics*; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015283:Citalopram / Q000493:pharmacokinetics*; D004347:Drug Interactions; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors