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 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 journalArticle

14 Citations (Scopus)

Abstract

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
JournalPsychopharmacology
Volume231
Issue number23
DOIs
StatePublished - 1 Jan 2014

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Serotonin Plasma Membrane Transport Proteins
Citalopram
Allosteric Site
Antidepressive Agents
Serotonin
Hindlimb Suspension
Calcium Carbonate

Keywords

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

Cite this

Jacobsen, Jacob P.R. ; Plenge, Per ; Sachs, Benjamin D. ; Pehrson, Alan ; Cajina, Manuel ; Du, Yunzhi ; Roberts, Wendy ; Rudder, Meghan L. ; Dalvi, Prachiti ; Robinson, Taylor J. ; O'Neill, Sharon P. ; Khoo, King S. ; Morillo, Connie Sanchez ; Zhang, Xiaodong ; Caron, Marc G. / The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse. In: Psychopharmacology. 2014 ; Vol. 231, No. 23. pp. 4527-4540.
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title = "The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse",
abstract = "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.",
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Jacobsen, JPR, Plenge, P, Sachs, BD, Pehrson, A, Cajina, M, Du, Y, Roberts, W, Rudder, ML, Dalvi, P, Robinson, TJ, O'Neill, SP, Khoo, KS, Morillo, CS, Zhang, X & Caron, MG 2014, 'The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse', Psychopharmacology, vol. 231, no. 23, pp. 4527-4540. https://doi.org/10.1007/s00213-014-3595-1

The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse. / Jacobsen, Jacob P.R.; Plenge, Per; Sachs, Benjamin D.; Pehrson, Alan; Cajina, Manuel; Du, Yunzhi; Roberts, Wendy; Rudder, Meghan L.; Dalvi, Prachiti; Robinson, Taylor J.; O'Neill, Sharon P.; Khoo, King S.; Morillo, Connie Sanchez; Zhang, Xiaodong; Caron, Marc G.

In: Psychopharmacology, Vol. 231, No. 23, 01.01.2014, p. 4527-4540.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse

AU - Jacobsen, Jacob P.R.

AU - Plenge, Per

AU - Sachs, Benjamin D.

AU - Pehrson, Alan

AU - Cajina, Manuel

AU - Du, Yunzhi

AU - Roberts, Wendy

AU - Rudder, Meghan L.

AU - Dalvi, Prachiti

AU - Robinson, Taylor J.

AU - O'Neill, Sharon P.

AU - Khoo, King S.

AU - Morillo, Connie Sanchez

AU - Zhang, Xiaodong

AU - Caron, Marc G.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

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KW - Allosteric

KW - Antidepressant

KW - Escitalopram

KW - Microdialysis

KW - R-citalopram

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