Blockade of the high-affinity norepinephrine transporter -NET- by the selective serotonin reuptake inhibitor escitalopram- an in vivo microdialysis study in mice-

Authors
H. Nguyen, B. Guiard, A. Bacq, D. David, I. David et al.

Lab
Université Paris-Sud XI, Faculté de Pharmacie, Lab. Neuropharmacologie, Châtenay-Malabry, France. ; Neuropharmacological. Res., Copenhagen, Denmark ; INSERM U952, Paris, France ; CNRS UMR 7224, Paris, France ; UPMC Univ Paris 06, Paris, France.

Journal
British Journal of Pharmacology

Abstract
Background and Purpose_ Escitalopram, the S(+)-enantiomer of citalopram is the most selective serotonin (5-HT) reuptake inhibitor approved. Although all serotonin selective reuptake inhibitors (SSRIs) increase extracellular levels of serotonin ([5-HT](ext) ), some of them also enhance, to a lower extent, extracellular levels of norepinephrine ([NE](ext) ). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. Experimental approach_ This study aimed at examining the effects of escitalopram, on both [5-HT](ext) and [NE](ext ) in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT(-/-) ) by using intracerebral microdialysis. In particular, the possibilities that escitalopram enhances [NE](ext) either by a direct mechanism involving the inhibition of the low- or high-affinity NE transporters, or by an indirect mechanism promoted by [5-HT](ext) elevation were explored. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT](ext) and/or [NE](ext) affected the antidepressant-like activity of escitalopram. Key results_ In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT](ext ) and [NE](ext) . As expected, escitalopram failed to increase cortical [5-HT](ext) in SERT(-/-) mice whereas its neurochemical effects on [NE](ext) persisted in these mutants. In WT mice submitted to the FST, escitalopram increased swimming parameter without affecting climbing behavior. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical NE and 5-HT uptake mediated by low-affinity monoamine transporters. . Conclusions and implications_ These experiments suggest that escitalopram enhances, although moderately, cortical [NE](ext) in vivo by a direct mechanism involving the inhibition of the high-affinity NE transporter (NET).

BIOSEB Instruments Used:
Forced Swimming Test: New FST DUAL SENSOR (BIO-FST-DSM)