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The effects of acute treatment with escitalopram on the different stages of contextual fear conditioning are reversed by atomoxetine

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Abstract

Rationale

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.

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Abbreviations

5-HT:

Serotonin

CR:

Conditioned fear response

CS:

Conditioned stimulus

DA:

Dopamine

NA:

Noradrenaline

NAT:

Noradrenaline transporter

SNRIs:

Selective noradrenaline reuptake inhibitors

SSRIs:

Selective serotonin reuptake inhibitors

5-HTT:

Serotonin transporter

US:

Unconditioned stimulus

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Acknowledgements

Liliana C. P. Montezinho was supported by a grant (SFRH/BPD/18389/2004) from Fundação para a Ciência e Tecnologia (F.C.T.), Portugal. The authors would like to thank Anette Frederiksen and Nina Guldhammer for their skillful technical assistance with the microdialysis studies in freely moving rats and Mary Dovlatyan and Chris Schaich for expert assistance with the occupancy determination and Kim Feijgin and Bettina Ullitz for their assistance with the locomotor activity studies.

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  1. Silke Miller

    Present address: Department of Neuroscience, Amgen Inc., One Amgen Center Dr., MS 29-2-B, Thousand Oaks, CA, 91320, USA

Authors and Affiliations

  1. Department of Neurophysiology, H. Lundbeck A/S, Ottiliavej 9, 2500, Copenhagen-Valby, Denmark

    Liliana P. Montezinho, Nanna Hovelsø Jensen, Louise Witten & Arne Mørk

  2. Department of Neuroscience, Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ, 07652-1431, USA

    Silke Miller

  3. Department of In vivo Neurobiology, H. Lundbeck A/S, Ottiliavej 9, 2500, Copenhagen-Valby, Denmark

    Niels Plath

  4. Department of Discovery ADME, H. Lundbeck A/S, Ottiliavej 9, 2500, Copenhagen-Valby, Denmark

    Jens-Jakob Karlsson

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  1. Liliana P. Montezinho
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Correspondence to Liliana P. Montezinho.

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Montezinho, L.P., Miller, S., Plath, N. et al. The effects of acute treatment with escitalopram on the different stages of contextual fear conditioning are reversed by atomoxetine. Psychopharmacology 212, 131–143 (2010). https://doi.org/10.1007/s00213-010-1917-5

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