Blockade of the high‐affinity noradrenaline transporter (NET) by the selective 5‐HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice. (18th December 2012)

• Record Type: Journal Article
• Authors: Nguyen, Hai T; Guiard, Bruno P; Bacq, Alexandre; David, Denis J; David, Indira; Quesseveur, Gaël; Gautron, Sophie; Sanchez, Connie; Gardier, Alain M
• Is Part Of: British journal of pharmacology. Volume 168:Number 1(2013:Jan.)
• Page Start: 103
• Page End: 116
• Publication Date: 2012-12-18
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/j.1476-5381.2012.01850.x
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <p> <bold>BACKGROUND AND PURPOSE</bold> Escitalopram, the S(+)‐enantiomer of citalopram is the most selective 5‐HT reuptake inhibitor approved. Although all 5‐HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5‐HT ([5‐HT]<sub>ext</sub>). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]<sub>ext</sub>). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined.</p> <p> <bold>EXPERIMENTAL APPROACH</bold> This study examined the effects of escitalopram, on both [5‐HT]<sub>ext</sub> and [NA]<sub>ext </sub>in the frontal cortex (FCx) of freely moving wild‐type (WT) and mutant mice lacking the 5‐HT transporter (SERT<sup>−/−</sup>) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]<sub>ext</sub>, either by a direct mechanism involving the inhibition of the low‐ or high‐affinity noradrenaline transporters, or by an indirect mechanism promoted by [5‐HT]<sub>ext</sub> elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5‐HT]<sub>ext</sub> and/or [NA]<sub>ext</sub> affected the antidepressant‐like activity of escitalopram.</p> <p> <bold>KEY RESULTS</bold> In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5‐HT]<sub>ext </sub>and [NA]<sub>ext</sub>. As expected, escitalopram failed to increase cortical [5‐HT]<sub>ext</sub> in SERT<sup>−/−</sup> mice, whereas its neurochemical effects on [NA]<sub>ext</sub> persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5‐HT uptake mediated by low‐affinity monoamine transporters.</p> <p> <bold>CONCLUSIONS AND IMPLICATIONS</bold> These experiments suggest that escitalopram enhances, although moderately, cortical [NA]<sub>ext</sub><italic>in vivo</italic> by a direct mechanism involving the inhibition of the high‐affinity noradrenaline transporter (NET).</p> </abstract>