In vivo investigation of escitalopram's allosteric site on the serotonin transporter

• Type of Material: Article
• Authors: Karen E. Murray, Emory University; Kerry Ressler, Emory University; Michael Owens, Emory University
• Language: English
• Date: 2016-02
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2015 Elsevier Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.pbb.2015.11.010
• Title of Journal or Parent Work: Pharmacology Biochemistry and Behavior
• Volume: 141
• Start Page: 50
• End Page: 57
• Grant/Funding Information: KEM has received partial stipend support during these projects from the National Institutes of Health National Institute on Drug Abuse [Grant 5T32-DA-015040-09] and National Institute of General Medical Sciences [Grant T32-GM-08605-14].; This work was financially supported by Lundbeck A/S (MJO and KJR) and an Emory University Research Council Award (MJO).
• Keywords: Serotonin transporter; Mice, Transgenic; Animals; Marble burying; Serotonin Uptake Inhibitors; SSRI; Serotonin Plasma Membrane Transport Proteins; Escitalopram; Tail suspension test; Citalopram; Mice; Allosteric; Allosteric Site
• Research Categories: Biology, Neuroscience; Psychology, Behavioral

Abstract

Escitalopram is a commonly prescribed antidepressant of the selective serotonin reuptake inhibitor class. Clinical evidence and mapping of the serotonin transporter (SERT) identified that escitalopram, in addition to its binding to a primary uptake-blocking site, is capable of binding to the SERT via an allosteric site that is hypothesized to alter escitalopram's kinetics at the SERT. The studies reported here examined the in vivo role of the SERT allosteric site in escitalopram action. A knockin mouse model that possesses an allosteric-null SERT was developed. Autoradiographic studies indicated that the knockin protein was expressed at a lower density than endogenous mouse SERT (approximately 10-30% of endogenous mouse SERT), but the knockin mice are a viable tool to study the allosteric site. Microdialysis studies in the ventral hippocampus found no measurable decrease in extracellular serotonin response after local escitalopram challenge in mice without the allosteric site compared to mice with the site (p = 0.297). In marble burying assays there was a modest effect of the absence of the allosteric site, with a larger systemic dose of escitalopram (10-fold) necessary for the same effect as in mice with intact SERT (p = 0.023). However, there was no effect of the allosteric site in the tail suspension test. Together these data suggest that there may be a regional specificity in the role of the allosteric site. The lack of a robust effect overall suggests that the role of the allosteric site for escitalopram on the SERT may not produce meaningful in vivo effects.