Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

Long, Nicole E. De; Barry, Eric J.; Pinelli, Christopher; Wood, Geoffrey A.; Hardy, Daniel B.; Morrison, Katherine M.; Taylor, Valerie H.; Gerstein, Hertzel C.; Holloway, Alison C.

doi:10.1016/j.taap.2015.03.006

Cited by 20 publications

(23 citation statements)

References 66 publications

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“…The therapeutic serum concentration in humans taking FLX ranges from 91 to 302 ng/ml; a comparable serum level was observed in rats given 8–12 mg/kg/day FLX (p.o. or by osmotic pump) (Capello et al, 2011; De Long et al, 2015; Margiotta‐Casaluci et al, 2014; Olivier et al, 2011b; U.S. Food and Drug Administration, 2001). Clinically effective doses of BUP in humans range from 589 to 1050 ng/ml; serum concentrations of BUP after 40 mg/kg/day (i.p.)…”

Section: Methodsmentioning

confidence: 99%

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open‐field activity in Sprague‐Dawley rats

Sprowles¹,

Hufgard

Gutierrez

et al. 2017

Intl J of Devlp Neuroscience

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Most antidepressants inhibit monoamine reuptake. Selective serotonin (5-HT) reuptake inhibitors (SSRIs) act on the 5-HT transporter (SERT) whereas norepinephrine-dopamine reuptake inhibitors (NDRIs) act on the norepinephrine and dopamine transporters. Epidemiological reports link SSRI use during pregnancy to an increased prevalence of autism spectrum disorder (ASD). We previously showed that perinatal exposure to the SSRI citalopram (CIT) results in rodent offspring that exhibit a number of behaviors consistent with an ASD-like phenotype. The present study examined the effect of perinatal exposure to CIT (at a lower dose), another SSRI, fluoxetine (FLX), and an NDRI, bupropion (BUP). Gravid Sprague-Dawley rats were subcutaneously injected twice per day (6h apart) with 5mg/kg CIT, 5mg/kg FLX, 15mg/kg BUP, or saline (SAL) from embryonic day (E) 6-21, and directly to the pups from postnatal day (P) 1-20. As adults, one male/female from each litter was given one of a series of tests. Both SSRI-exposed groups showed spatial learning deficits in Morris and radial water mazes, increased marble burying, increased acoustic startle, hypoactivity, and attenuated activity to the stimulating effect of the NMDA-R antagonist MK-801. The BUP-exposed group showed a reduction in elevated zero-maze quadrant entries and increased stimulated open-field activity following (+)-amphetamine challenge. These results reinforce concern about the use of antidepressants during pregnancy and highlight how the two classes of drugs produce different constellations of effects with more effects associated with the SSRIs. Further investigation into how antidepressants alter brain development leading to enduring adverse neurobehavioral effects is warranted.

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Section: Methodsmentioning

confidence: 99%

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open‐field activity in Sprague‐Dawley rats

Sprowles¹,

Hufgard

Gutierrez

et al. 2017

Intl J of Devlp Neuroscience

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“…Nulliparous 200‐250 g female Wistar rats (Harlan, Indianapolis, Indiana) were conventionally housed in polycarbonate microisolator cages under controlled lighting (12:12 L:D), humidity (40–50%), and temperature (22°C) with ad libitum access to water and standard chow diet (Teklad 22/5 rodent diet; Envigo, Indianapolis, Indiana). Dams were randomly assigned to receive vehicle (CON; N = 15) or 10 mg/kg/day fluoxetine hydrochloride (FLX; N = 15; Toronto Research Chemicals, Toronto, Ontario) orally in flavored gelatin cubes from 14 days prior to mating until weaning (postnatal day 21; PND21) as previously described (De Long et al, ). The dose of fluoxetine was chosen based on previous studies (Capello et al, ; Hui, Huang, Ebbert, & Bina, ) to achieve serum fluoxetine levels in the rat which are representative of the median serum concentration of fluoxetine (i.e., 450 nmol/L) reported in humans (Olivier et al, ; Sit, Perel, Helsel, & Wisner, ).…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, in animal models, activation of the NLRP3 inflammasome has been shown to play a role in the progression of NAFLD to NASH (reviewed in [Wan et al, ]). This is of great interest as we have reported that fetal and neonatal exposure to fluoxetine increased the proportion of offspring with mild‐to‐moderate NASH (De Long et al, ). Moreover, as fluoxetine has been shown to increase production of IL1β (Alboni et al, ), which is mainly dependent on activation of the NLRP3 inflammasome (Martinon, Burns, & Tschopp, ), these data suggest that the increased prevalence of NASH in offspring born to fluoxetine‐exposed dams may be a result of dysregulated de novo lipogenesis and activation of the NLRP3 inflammasome.…”

Section: Introductionmentioning

confidence: 97%

“…In support of this hypothesis, Grzeskowiak et al (2013) reported that male offspring exposed prenatally to an SSRI had an increased risk of being overweight by 7 years of age. Similarly, our lab has demonstrated in a rodent model that fetal and neonatal exposure to the SSRI antidepressant fluoxetine results in metabolic perturbations in adulthood including increased adiposity and insulin resistance (De Long et al, 2015). Moreover, fluoxetine exposure resulted in increased hepatic triglyceride content; a hallmark of nonalcoholic fatty liver disease (NAFLD) (De Long et al, 2015).…”

Section: Introductionmentioning

confidence: 97%

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Increased incidence of non‐alcoholic fatty liver disease in male rat offspring exposed to fluoxetine during fetal and neonatal life involves the NLRP3 inflammasome and augmented de novo hepatic lipogenesis

Long

Hardy

et al. 2017

J of Applied Toxicology

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Up to 10% of women take selective serotonin reuptake inhibitors (SSRI) during pregnancy. Children exposed to SSRIs in utero have an increased risk of being overweight suggesting that fetal exposure to SSRIs can cause permanent metabolic changes. We have previously shown in rats that fetal and neonatal exposure to the SSRI antidepressant fluoxetine results in metabolic perturbations including increased hepatic triglyceride content; a hallmark of non‐alcoholic fatty liver disease (NAFLD). Therefore, the aim of this study was to identify the mechanism(s) underlying the fluoxetine‐induced increase in intrahepatic triglyceride content. Female nulliparous Wistar rats were given vehicle or fluoxetine (10 mg/kg/day) orally for 2 weeks prior to mating until weaning. At 6 months of age, we assessed whether SSRI exposure altered components of the hepatic triglyceride biosynthesis pathway in the offspring and examined the molecular mechanisms underlying these changes. Male SSRI‐exposed offspring had a significant increase in the steady‐state mRNA levels of Elovl6 and Dgat1 and core components of the NLRP3 inflammasome (apoptosis‐associated speck‐like protein containing a caspase activation recruitment domain [ASC] and caspase‐1). Augmented expression of Asc in the SSRI‐exposed offspring coincided with increased histone acetylation in the proximal promoter region. Given that we have previously demonstrated that antenatal exposure to SSRIs can lead to fatty liver in the offspring, this raises concerns regarding the long‐term metabolic sequelae of fetal SSRI exposure. Moreover, this study suggests that elevated hepatic triglyceride levels observed in the SSRI‐exposed offspring may be due, in part, to activation of the NLRP3 inflammasome and augmentation of de novo lipogenesis.

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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: 96%

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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Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

Cited by 20 publications

References 66 publications

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open‐field activity in Sprague‐Dawley rats

Differential effects of perinatal exposure to antidepressants on learning and memory, acoustic startle, anxiety, and open‐field activity in Sprague‐Dawley rats

Increased incidence of non‐alcoholic fatty liver disease in male rat offspring exposed to fluoxetine during fetal and neonatal life involves the NLRP3 inflammasome and augmented de novo hepatic lipogenesis

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

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