The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse

Jacob P.R. Jacobsen, Per Plenge, Benjamin D. Sachs, Alan L. Pehrson, Manuel Cajina, Yunzhi Du, Wendy Roberts, Meghan L. Rudder, Prachiti Dalvi, Taylor J. Robinson, Sharon P. O'Neill, King S. Khoo, Connie Sanchez Morillo, Xiaodong Zhang, Marc G. Caron

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Rationale: 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, thereby curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence antidepressant 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 hereof.

Objectives: 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 (hSERTWT) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERTALI/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.

Original languageEnglish
Pages (from-to)4527-4540
Number of pages14
Issue number23
StatePublished - Dec 2014

ASJC Scopus subject areas

  • Pharmacology


  • 5-HT
  • Allosteric
  • Antidepressant
  • Escitalopram
  • Microdialysis
  • R-citalopram

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