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

Olivier, Jocelien; Vallès, Astrid; Heesch, Floor van; Afrasiab-Middelman, Anthonieke; Roelofs, Joris J. T. H.; Jonkers, Marloes; Peeters, Elke Joan; Korte-Bouws, G.A.H.; Dederen, Jos; Kiliaan, Amanda J.; Martens, Gerard J.M.; Schubert, Dirk W.; Homberg, Judith R.

doi:10.1007/s00213-011-2299-z

Cited by 134 publications

(182 citation statements)

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“…During early life, serotonergic neurons are among the earliest to be generated, and 5-HT has an important role in different processes pivotal for neuronal growth and maturation (Gaspar et al, 2003). Indeed, blockade of SERT during fetal life of rats can lead to negative outcomes on brain function and behavior, including behavioral despair and anxiety-like behavior (Lisboa et al, 2007;Olivier et al, 2011). Moreover, pharmacological blockade of SERT during early post-natal life (PND 4-21) results in increased immobility time in the Figure 3 Chronic duloxetine treatment modulates the levels of neuronal PAS domain protein 4 (Npas4) and aryl hydrocarbon receptor nuclear translocator 2 (Arnt2) gene expression in serotonin transporter (SERT) À/À rats.…”

Section: Discussionmentioning

confidence: 99%

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Guidotti

Calabrese

Auletta

et al. 2011

Neuropsychopharmacol

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Alterations of the serotonergic system are involved in the pathophysiology of mood disorders and represent an important target for its pharmacological treatment. Genetic deletion of the serotonin transporter (SERT) in rodents leads to an anxious and depressive phenotype, and is associated with reduced neuronal plasticity as indicated by decreased brain-derived neurotrophic factor (Bdnf) expression levels. One of the transcription factors regulating Bdnf is the neuronal PAS domain protein 4 (Npas4), which regulates activitydependent genes and neuroprotection, and has a critical role in the development of GABA synapses. On the basis of these premises, we investigated the expression of Npas4 and GABAergic markers in the hippocampus and prefrontal cortex of homozygous (SERT À/À ) and heterozygous (SERT + /À ) knockout rats, and analyzed the effect of long-term duloxetine treatment on the expression of these targets. We found that Npas4 expression was reduced in both the brain structures of adult SERT + /À and SERT À/À animals. This effect was already present in adolescent SERT À/À , and could be mimicked by prenatal exposure to the antidepressant fluoxetine. Moreover, SERT À/À rats showed a strong impairment of the GABAergic system, as indicated by the reduction of several markers, including the vesicular transporter (Vgat), glutamic acid decarboxylase-67 (Gad67), the receptor subunit GABA A receptor, gamma 2 (GABA A -g2), and calciumbinding proteins that label subgroups of the GABAergic neurons. Interestingly, chronic treatment with the antidepressant duloxetine was able to restore the physiological levels of Npas4 and GABAergic markers in SERT À/À rats, although some differences in the modulation of GABAergic genes exist between hippocampus and prefrontal cortex. Our results demonstrate that SERT knockout rats, an animal model of mood disorders, have reduced Npas4 expression that correlates with decreased expression of Bdnf exon I and IV. These changes lead to an impairment of the GABAergic system that may contribute to the anxious and depressive phenotype associated with inherited SERT downregulation.

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Section: Discussionmentioning

confidence: 99%

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Guidotti

Calabrese

Auletta

et al. 2011

Neuropsychopharmacol

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“…Conversely, two studies found that perinatal SSRIs increased weight at the juvenile stage [84] and adulthood [52], while other studies have failed to find a difference in weight in offspring at pre-weaning [86], at adulthood [84], from pre-weaning into the juvenile stage [13,18,54,56], and from pre-weaning into adulthood [16,52,59,88]. In terms of other types of animal studies, gestational SSRIs in sheep reduced weight of lambs at P2 and P3, but with no difference at P5 [60].…”

Section: Animal Studiesmentioning

confidence: 95%

“…Studies have found that SSRIs during gestation reduced weight at pre-weaning [43,45,46,84], at pre-weaning into the juvenile stage [44,58], at the juvenile stage [85], or at adulthood [48,86].…”

Section: Animal Studiesmentioning

confidence: 99%

Perinatal selective serotonin reuptake inhibitor (SSRI) effects on body weight at birth and beyond: A review of animal and human studies

Hutchison

Mâsse

Pawluski

et al. 2018

Reproductive Toxicology

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. Perinatal selective serotonin reuptake inhibitor (SSRI) effects on body weight at birth and beyond A review of animal and human studies. Reproductive Toxicology, Elsevier, 2018, 77, pp.109-121. 10 Highlights  Our paper reviews our current understanding of the impact of prenatal SSRI exposure on weight and growth using both human and animal findings.  Our review extends the previously published review paper by Grzeskowiak and colleagues in Repro Tox in 2012 by including findings beyond infancy, the impact of maternal mood -pre and post natal, and given that the majority our 5HT is in the gastrointestinal (GI) system we speculate that altering 5HT signaling, via SSRI exposure might have an impact on GI function and later weight gain.  With recent advances in our understanding of the gut-brain axis and the role of 5HT, we raise critical questions about how weight and growth outcomes might be related to SSRI induced changes in the GI microbiome.  Our paper provides an updated review of the literature (e.g., Leuner et al 2014;Nezvalová-Henriksen et al., 2016), with a particular focus on weight related outcomes beyond birth, developmental aspects of SSRI exposure that might also impact weight and growth, as well as provides detailed suggestions for future research. AbstractThe long-term impact of selective serotonin reuptake inhibitor (SSRI) antidepressant treatment during pregnancy and postpartum on offspring outcomes is still not clear. Specifically, perinatal SSRI exposure may have long-term consequences for body weight and related health outcomes in the newborn period and beyond. This review focuses on the impact of perinatal SSRI exposure on weight using human and animal findings. The impact of maternal mood is also explored. We propose potential mechanisms for weight changes, including how early alterations in serotonin signaling may have implications for weight via changes in metabolism and motor development.As the majority of serotonin is in the gastrointestinal (GI) system we also speculate that perinatal SSRI exposure might alter the brain-gut relationship, via the microbiome, leading to changes in feeding behavior and weight.

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“…Following perinatal exposure to Flx, changes observed in adult mice and rats are not always disadvantageous. Flx-exposed rats sometimes perform better than controls, demonstrating better coordination and balance, superior emotional and spatial memory in adolescence [17], and better emotional memory in adulthood [18]. Other findings include decreased anxiety [19], reduced impulsivity [20], and less depressive behaviour [19,20,21] in adult mice.…”

Section: Introductionmentioning

confidence: 99%

Increased Aggression, Improved Spatial Memory, and Reduced Anxiety-Like Behaviour in Adult Male Mice Exposed to Fluoxetine Early in Life

Kiryanova

Dyck

2014

Dev Neurosci

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Rationale: Fluoxetine (Flx; brand names Prozac, Sarafem, Rapiflux), a selective serotonin reuptake inhibitor, is prescribed for the treatment of depression in pregnant women; however, this commonly prescribed medication could affect fetal brain development as Flx crosses the placenta. The available data concerning the anatomical and behavioural consequences of perinatal exposure to Flx during early development on adult behaviour are limited and often contradictory. Objectives: To further delineate the long-term behavioural effects of altering 5-HT during development, we examined the effects of perinatal Flx exposure on the behaviour of male mice as adults. Methods: Dams were treated with approximately 25 mg/kg/day of Flx from embryonic day 15 to postnatal day 12, and the behaviour of the adult offspring was assessed. Results: We found that perinatal Flx exposure leads to increased aggression, improved spatial memory, and reduced anxiety-like behaviour. This exposure did not cause memory deficits, changes in sensory processing, or changes in gross motor function. Conclusions: Our results suggest that while perinatal exposure to Flx may have long-term effects on adult behaviour, these effects appear limited and not necessarily detrimental.

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

Abstract: Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT(1A) receptor signaling.

Cited by 134 publications

References 72 publications

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Developmental Influence of the Serotonin Transporter on the Expression of Npas4 and GABAergic Markers: Modulation by Antidepressant Treatment

Perinatal selective serotonin reuptake inhibitor (SSRI) effects on body weight at birth and beyond: A review of animal and human studies

Increased Aggression, Improved Spatial Memory, and Reduced Anxiety-Like Behaviour in Adult Male Mice Exposed to Fluoxetine Early in Life

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