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Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring

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Abstract

Rationale

Fluoxetine (Prozac®) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus.

Objectives

The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats.

Methods

Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored.

Results

Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 μg/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT1A agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls.

Conclusions

Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT1A receptor signaling.

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Abbreviations

5-HT:

Serotonin

5-HTT:

Serotonin transporter

5-HTT−/− :

Serotonin transporter knockout

CE:

Copulatory efficiency

CPA:

Conditioned place aversion

E:

Embryonic day

ECG:

Electrocardiogram

EL:

Ejaculatory latency

GD:

Gestational day

I:

Intromission

I.P.:

Intraperitoneal

M:

Mount

PEL:

Postejaculatory latency

PND:

Postnatal day

SSRI:

Selective serotonin reuptake inhibitor

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Acknowledgments

We thank Lars Valke, Mariëlle Winters, Loes Schiphouwer, and Anneke Sloet for their practical assistance. This research was financially supported by the Donders Centre for Neuroscience, Radboud University Nijmegen, The Netherlands, and a grant (no. 433-09-311) from The Netherlands Organisation for Scientific Research (NWO), awarded to J. Homberg. The Donders Centre for Neuroscience and NWO had no further role in the design of the study, in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication. The experiments comply with the current laws of the Netherlands.

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The authors declare to have no conflicts of interest

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Authors and Affiliations

  1. Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21 (route 126), 6525, EZ, Nijmegen, The Netherlands

    Jocelien D. A. Olivier, Floor van Heesch, Anthonieke Afrasiab-Middelman, Janneke J. P. M. Roelofs, Marloes Jonkers, Elke Joan Peeters, Dirk Schubert & Judith R. Homberg

  2. Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Department of Molecular Animal Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Jocelien D. A. Olivier, A. Vallès & Gerard J. Martens

  3. Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Rudolf Magnus Institute of Neuroscience, Utrecht University, Utrecht, The Netherlands

    Gerdien A. H. Korte-Bouws

  4. Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Department of Anatomy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Jos P. Dederen & Amanda J. Kiliaan

  5. Department of Neurocognition, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, The Netherlands

    A. Vallès

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  1. Jocelien D. A. Olivier
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  2. A. Vallès
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  3. Floor van Heesch
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Correspondence to Judith R. Homberg.

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Olivier, J.D.A., Vallès, A., van Heesch, F. et al. Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring. Psychopharmacology 217, 419–432 (2011). https://doi.org/10.1007/s00213-011-2299-z

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