title: Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice.
abstract: OBJECTIVE
  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](ext)). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA](ext)). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined.
  
  
  METHODS
  This study examined the effects of escitalopram, on both [5-HT](ext) and [NA](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. We explored the possibilities that escitalopram enhances [NA](ext), 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](ext) elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT](ext) and/or [NA](ext) affected the antidepressant-like activity of escitalopram.
  
  
  RESULTS
  In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT](ext) and [NA](ext). As expected, escitalopram failed to increase cortical [5-HT](ext) in SERT(-/-) mice, whereas its neurochemical effects on [NA](ext) 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.
  
  
  CONCLUSIONS
  These experiments suggest that escitalopram enhances, although moderately, cortical [NA](ext) in vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET).
authors.affiliation: Laboratoire de Neuropharmacologie, Faculté de Pharmacie, Université Paris-Sud XI, Châtenay-Malabry, France.
authors.forename: Hai T
authors.initials: HT
authors.lastname: Nguyen
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bacq
authors.forename: Denis J
authors.initials: DJ
authors.lastname: David
authors.forename: Indira
authors.initials: I
authors.lastname: David
authors.forename: Gaël
authors.initials: G
authors.lastname: Quesseveur
authors.forename: Sophie
authors.initials: S
authors.lastname: Gautron
authors.forename: Connie
authors.initials: C
authors.lastname: Sanchez
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D017551:Microdialysis; D023421:Models, Animal; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013550:Swimming; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D015283:Citalopram; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors