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

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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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Acknowledgements

This study was supported in part by H. Lundbeck A/S via an investigator-initiated Sponsored Research Agreement with Duke University. BDS was the recipient of a Minority Supplement award from the National Institutes of Health (MH79201-03S1) and is currently the recipient of an NRSA postdoctoral fellowship (F32-MH093092). JPRJ is the grateful recipient of an individual grant from The Lundbeck Foundation of Denmark. The authors are grateful to Dr. Hans Petersen for performing chiral analysis of es- and R-citalopram

Conflict of interest

ALP, MC and CS are employees of Lundbeck Research, USA. MGC has consulted for Lundbeck and received compensation. Remaining authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Cell Biology, Duke University Medical Center, PO Box 3287, Durham, NC, 27710, USA

    Jacob P. R. Jacobsen, Benjamin D. Sachs, Yunzhi Du, Wendy Roberts, Meghan L. Rudder, Prachiti Dalvi, Taylor J. Robinson & Marc G. Caron

  2. Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Per Plenge

  3. Lundbeck Research USA, Paramus, NJ, USA

    Alan L. Pehrson, Manuel Cajina & Connie Sanchez Morillo

  4. Neuroscience and Behavioral Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore

    Sharon P. O’Neill, King S. Khoo & Xiaodong Zhang

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  1. Jacob P. R. Jacobsen
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Correspondence to Marc G. Caron.

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Jacobsen, J.P.R., Plenge, P., Sachs, B.D. et al. The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse. Psychopharmacology 231, 4527–4540 (2014). https://doi.org/10.1007/s00213-014-3595-1

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