title: The effects of acute treatment with escitalopram on the different stages of contextual fear conditioning are reversed by atomoxetine.
abstract: BACKGROUND
  Although the antidepressant and anxiolytic effects of selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors are well-documented, less is known about their cognitive effects.
  
  
  OBJECTIVE
  Escitalopram, a selective serotonin reuptake inhibitor, and atomoxetine, a selective noradrenaline reuptake inhibitor, were used to evaluate the interaction between noradrenergic and serotonergic neurotransmission in the modulation of contextual fear conditioning in rats.
  
  
  METHODS
  Contextual fear-conditioning test was used to investigate the acute effects of escitalopram, alone or in combination with atomoxetine, in different stages of learning and memory in rats. Furthermore, microdialysis in freely moving animals was used to investigate the effect of escitalopram on serotonin, dopamine, and noradrenaline levels in the rat hippocampus.
  
  
  RESULTS
  Escitalopram significantly increased conditioned responses when applied before the acquisition, but decreased responses, when applied before the recall test. When administered during memory consolidation, escitalopram dose-dependently enhanced conditioned responding. These effects were blocked by atomoxetine. Escitalopram (at a dose that affects memory consolidation) increased hippocampal serotonin levels fourfold without changing dopamine or noradrenaline. Atomoxetine, at dose levels that blocked the effects of escitalopram on contextual fear conditioning, increased the extracellular levels of noradrenaline eightfold but did not change dopamine or serotonin. A combined treatment of escitalopram and atomoxetine caused a significant attenuation of escitalopram-induced increase in serotonin levels, while noradrenaline levels were not affected.
  
  
  CONCLUSIONS
  These findings indicate that escitalopram affects fear memory in rats, likely modulated by increases in serotonin levels in the brain. This effect is impaired by atomoxetine, probably due to a noradrenaline-mediated decrease in serotonin levels. Further studies are warranted to study the effects of potential differences among antidepressant therapies on long-term cognitive outcomes.
authors.affiliation: Department of Neurophysiology, H Lundbeck A/S, Ottiliavej 9, 2500, Copenhagen-Valby, Denmark. LCPM@lundbeck.com
authors.forename: Liliana P
authors.initials: LP
authors.lastname: Montezinho
authors.forename: Silke
authors.initials: S
authors.lastname: Miller
authors.forename: Niels
authors.initials: N
authors.lastname: Plath
authors.forename: Nanna Hovelsø
authors.initials: NH
authors.lastname: Jensen
authors.forename: Jens-Jakob
authors.initials: JJ
authors.lastname: Karlsson
authors.forename: Louise
authors.initials: L
authors.lastname: Witten
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D015283:Citalopram / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D005239:Fear / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D015283:Citalopram; D004298:Dopamine; D009638:Norepinephrine; D011437:Propylamines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors