Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring |
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| Affiliation: | 1. School for Mental Health and Neuroscience (MHeNS), Maastricht University, European Graduate School of Neuroscience (EURON), Universiteitssingel 50, P.O. box 616, 6200, MD, Maastricht, The Netherlands;2. Center for Psychiatry and Neuroscience, INSERM, U894, University Pierre and Marie Curie, Paris, France;3. University of Liege, GIGA-Neurosciences, 1 avenue de l''Hôpital (Bat. B36), B-4000 Liège, Belgium;4. Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Radboud University Medical Centre, Department of Cognitive Neuroscience, Geert Grooteplein 21, 6525 EZ Nijmegen, The Netherlands;5. Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080 Wuerzburg, Germany;1. Department of Biosciences, University of Milan, via Celoria 26, Milan, Italy;2. Research and Conservation Department, Parco Natura Viva, Verona, Italy |
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| Abstract: | A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague–Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress + Vehicle, 2) No Stress + Fluoxetine, 3) Prenatal Stress + Vehicle, and 4) Prenatal Stress + Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect–related behaviors and their underlying molecular mechanisms. |
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