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

Journal Article (Journal Article)

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, 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. 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 (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.

Full Text

Duke Authors

Cited Authors

  • Jacobsen, JPR; Plenge, P; Sachs, BD; Pehrson, AL; Cajina, M; Du, Y; Roberts, W; Rudder, ML; Dalvi, P; Robinson, TJ; O'Neill, SP; Khoo, KS; Morillo, CS; Zhang, X; Caron, MG

Published Date

  • December 2014

Published In

Volume / Issue

  • 231 / 23

Start / End Page

  • 4527 - 4540

PubMed ID

  • 24810106

Pubmed Central ID

  • PMC4346315

Electronic International Standard Serial Number (EISSN)

  • 1432-2072

Digital Object Identifier (DOI)

  • 10.1007/s00213-014-3595-1


  • eng

Conference Location

  • Germany