Developmental Fluoxetine Exposure Normalizes the Long-Term Effects of Maternal Stress on Post-Operative Pain in Sprague-Dawley Rat Offspring

Early life events can significantly alter the development of the nociceptive circuit. In fact, clinical work has shown that maternal adversity, in the form of depression, and concomitant selective serotonin reuptake inhibitor (SSRI) treatment influence nociception in infants. The combined effects of maternal adversity and SSRI exposure on offspring nociception may be due to their effects on the developing hypothalamic-pituitary-adrenal (HPA) system. Therefore, the present study investigated long-term effects of maternal adversity and/or SSRI medication use on nociception of adult Sprague-Dawley rat offspring, taking into account involvement of the HPA system. Dams were subject to stress during gestation and were treated with fluoxetine (2×/5 mg/kg/day) prior to parturition and throughout lactation. Four groups of adult male offspring were used: 1. Control+Vehicle, 2. Control+Fluoxetine, 3. Prenatal Stress+Vehicle, 4. Prenatal Stress+Fluoxetine. Results show that post-operative pain, measured as hypersensitivity to mechanical stimuli after hind paw incision, was decreased in adult offspring subject to prenatal stress alone and increased in offspring developmentally exposed to fluoxetine alone. Moreover, post-operative pain was normalized in prenatally stressed offspring exposed to fluoxetine. This was paralleled by a decrease in corticosteroid binding globulin (CBG) levels in prenatally stressed offspring and a normalization of serum CBG levels in prenatally stressed offspring developmentally exposed to fluoxetine. Thus, developmental fluoxetine exposure normalizes the long-term effects of maternal adversity on post-operative pain in offspring and these effects may be due, in part, to the involvement of the HPA system

Perinatal fluoxetine prevents the effect of pre-gestational maternal stress on 5-HT in the PFC, but maternal stress has enduring effects on mPFC synaptic structure in offspring

Maternal affective disorders are frequently treated with selective serotonin reuptake inhibitor medications (SSRIs); with up to 10% of women being prescribed these medications during pregnancy. Infant development depends on the early serotonergic environment, which is altered by perinatal SSRIs, raising concern about how these medications affect neural outcomes. While clinical and preclinical research suggests an impact of SSRIs on the developing brain, more research is needed to determine the effects on neuroplasticity, the serotonergic system, and the hypothalamic-pituitary-adrenal axis in neural regions mediating behavior. The current work investigated the effects of the SSRI, fluoxetine, on the serotonergic system in the prefrontal cortex (PFC) during pre-adolescence, and changes to synaptic markers and glucocorticoid receptor density in the cingulate cortex (medial PFC) of pre-adolescent and adult Sprague-Dawley male and female rats. To model aspects of Perinatal Depression and maternal anxiety, pre-gestational maternal stress was used resulting in male and female offspring from 4 groups: 1) control, 2) perinatal fluoxetine exposed, 3) pre-gestational maternal stress exposed, and 4) pre-gestational maternal stress + fluoxetine. Perinatal fluoxetine prevented the effects of maternal stress on 5-HT levels and 5-HT turnover ratio in the PFC of pre-adolescent offspring, particularly in females. However, pre-gestational stress reduced synaptophysin and PSD-95 densities in the cingulate cortex, effects that were more pronounced in males. Interestingly, perinatal fluoxetine exposure reduced GR density in adult males in this same brain area. Together, results show differential effects of perinatal SSRIs and pre-gestational maternal stress on neurodevelopment in the PFC of males and females. © 2017 Elsevier Lt

Sex matters in neuroscience and neuropsychopharmacology

Prevalence and symptoms of most psychiatric and neurological disorders differ in men and women and there is substantial evidence that their neurobiological basis and treatment also differ by sex. This special issue sought to bring together a series of empirical papers and targeted reviews to highlight the diverse impact of sex in neuroscience and neuropsychopharmacology. This special issue emphasizes the diverse impact of sex in neuroscience and neuropsychopharmacology, including 9 review papers and 17 research articles highlighting investigation in different species (zebrafish, mice, rats, and humans). Each contribution covers scientific topics that overlap with genetics, endocrinology, cognition, behavioral neuroscience, neurology, and pharmacology. Investigating the extent to which sex differences can impact the brain and behavior is key to moving forward in neuroscience research. © 2020 Federation of European Neuroscience Societies and John Wiley & Sons Lt

Perinatal fluoxetine prevents the effect of pre-gestational maternal stress on 5-HT in the PFC, but maternal stress has enduring effects on mPFC synaptic structure in offspring

International audienceMaternal affective disorders are frequently treated with selective serotonin reuptake inhibitor medications (SSRIs); with up to 10% of women being prescribed these medications during pregnancy. Infant development depends on the early serotonergic environment, which is altered by perinatal SSRIs, raising concern about how these medications affect neural outcomes. While clinical and preclinical research suggests an impact of SSRIs on the developing brain, more research is needed to determine the effects on neuroplasticity, the serotonergic system, and the hypothalamic-pituitary-adrenal axis in neural regions mediating behavior. The current work investigated the effects of the SSRI, fluoxetine, on the serotonergic system in the prefrontal cortex (PFC) during pre-adolescence, and changes to synaptic markers and glucocorticoid receptor density in the cingulate cortex (medial PFC) of pre-adolescent and adult Sprague-Dawley male and female rats. To model aspects of Perinatal Depression and maternal anxiety, pre-gestational maternal stress was used resulting in male and female offspring from 4 groups: 1) control, 2) perinatal fluoxetine exposed, 3) pre-gestational maternal stress exposed, and 4) pre-gestational maternal stress + fluoxetine. Perinatal fluoxetine prevented the effects of maternal stress on 5-HT levels and 5-HT turnover ratio in the PFC of pre-adolescent offspring, particularly in females. However, pre-gestational stress reduced synaptophysin and PSD-95 densities in the cingulate cortex, effects that were more pronounced in males. Interestingly, perinatal fluoxetine exposure reduced GR density in adult males in this same brain area. Together, results show differential effects of perinatal SSRIs and pre-gestational maternal stress on neurodevelopment in the PFC of males and females

Long-term corticosterone exposure decreases insulin sensitivity and induces depressive-like behaviour in the C57BL/6NCrl mouse

Chronic stress or long-term administration of glucocorticoids disrupts the hypothalamus-pituitary-adrenal system leading to continuous high levels of glucocorticoids and insulin resistance (IR). This pre-diabetic state can eventually develop into type 2 diabetes mellitus and has been associated with a higher risk to develop depressive disorders. The mechanisms underlying the link between chronic stress, IR and depression remains unclear. The present study aimed to establish a stress-depression model in mice to further study the effects of stress-induced changes upon insulin sensitivity and behavioural consequences. A pilot study was conducted to establish the optimal administration route and a pragmatic measurement of IR. Subsequently, 6-month-old C57BL/6NCrl mice were exposed to long-term oral corticosterone treatment via the drinking water. To evaluate insulin sensitivity changes, blood glucose and plasma insulin levels were measured at different time-points throughout treatment and mice were behaviourally assessed in the elevated zero maze (EZM), forced swimming test (FST) and open field test to reveal behavioural changes. Long-term corticosterone treatment increased body weight and decreased insulin sensitivity. The latter was revealed by a higher IR index and increased insulin in the plasma, whereas blood glucose levels remained unchanged. Corticosterone treatment induced longer immobility times in the FST, reflecting depressive-like behaviour. No effects were observed upon anxiety as measured in the EZM. The effect of the higher body weight of the CORT treated animals at time of testing did not influence behaviour in the EZM or FST, as no differences were found in general locomotor activity. Long-term corticosterone treatment via the drinking water reduces insulin sensitivity and induces depressive-like behaviour in the C57BL/6 mouse. This mouse model could thus be used to further explore the underlying mechanisms of chronic stress-induced T2DM and its association with increased prevalence of major depressive disorder on the short-term and other behavioural adaptations on the longer term

Gestational stress and fluoxetine treatment differentially affect plasticity, methylation and serotonin levels in the PFC and hippocampus of rat dams

Women are more likely to develop depression during childbearing years with up to 20% of women suffering from depression during pregnancy and in the postpartum period. Increased prevalence of depression during the perinatal period has resulted in frequent selective serotonin reuptake inhibitor (SSRI) antidepressant treatment; however the effects of such medications on the maternal brain remain limited. Therefore, the aim of the present study is to investigate the effects of the SSRI medication, fluoxetine, on neurobiological differences in the maternal brain. To model aspects of maternal depression, gestational stress was used. Sprague-Dawley rat dams were exposed to either gestational stress and/or fluoxetine (5 mg/kg/day) to form the following four groups: 1. Control + Vehicle, 2. Stress + Vehicle, 3. Control + Fluoxetine, and 4. Stress + Fluoxetine. At weaning maternal brains were collected. Main findings show that gestational stress alone increased synaptophysin and serotonin metabolism in the cingulate cortex2 region of the cortex while fluoxetine treatment after stress normalized these effects. In the hippocampus, fluoxetine treatment, regardless of gestational stress exposure, decreased both global measures of methylation in the dentate gyrus, as measured by Dnmt3a immunoreactivity, as well as serotonin metabolism. No further changes in synaptophysin, PSD-95, or Dnmt3a immunoreactivity were seen in the cortical or hippocampal areas investigated. These findings show that gestational stress and SSRI medication affect the neurobiology of the maternal brain in a region-specific manner. This work adds to a much needed area of research aimed at understanding neurobiological changes associated with maternal depression and the role of SSRI treatment in altering these changes in the female brain. © 2016 IBRO

Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning

Selective serotonin reuptake inhibitor medication exposure during the perinatal period can have a long term impact in adult offspring on neuroplasticity and the serotonergic system, but the impact of these medications during early development is poorly understood. The aim of this study was to determine the effects of developmental exposure to the SSRI, fluoxetine, on the serotonergic system, dopaminergic system, and synaptophysin density in the prefrontal cortex and hippocampus, as well as number of immature neurons in the dentate gyrus, in juvenile rat offspring at weaning. To model aspects of maternal depression, prenatal restraint stress was used. Sprague-Dawley rat offspring were exposed to either prenatal stress and/or fluoxetine. Main findings show that developmental fluoxetine exposure to prenatally stressed offspring decreased 5-HT and 5-HIAA levels and altered the dopaminergic system in the hippocampus. Prenatal stress, regardless of fluoxetine, increased synaptophysin density in the PFC. This work indicates that early exposure to maternal stress and SSRI medication can alter brain monoamine levels and synaptophysin density in offspring at weaning. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 315-327, 2016

Perinatal fluoxetine effects on social play, the HPA system, and hippocampal plasticity in pre-adolescent male and female rats: Interactions with pre-gestational maternal stress

Selective serotonin reuptake inhibitor medications (SSRIs) are the first lines of treatment for maternal affective disorders, and are prescribed to up to 10% of pregnant women. Concern has been raised about how perinatal exposure to these medications affect offspring neurobehavioral outcomes, particularly those related to social interactions, as recent research has reported conflicting results related to autism spectrum disorder (ASD) risk in children prenatally exposed to SSRIs. Therefore, the aim of this work was to investigate the effects of perinatal exposure to the SSRI fluoxetine on social play behaviors and the hypothalamic pituitary adrenal system, using a model of pre-gestational maternal stress. We also investigated synaptic proteins in the CA2, CA3, and dentate gyrus of the hippocampus, as well as number of immature neurons in the granule cell layer, as both measures of plasticity in the hippocampus have been linked to social behaviors. In pre-adolescent male and female Sprague-Dawley rat offspring, main findings show that perinatal fluoxetine prevents the negative effect of maternal stress on sibling play behavior. However, perinatal fluoxetine increased social aggressive play with a novel conspecific in both sexes and decreased time grooming a novel conspecific in males only. Perinatal fluoxetine also increased serum corticosteroid binding globulin levels, 5-HT levels in the hippocampus, and pre-synaptic density assessed via synaptophysin in the dentate gyrus. Social interaction was significantly correlated with changes in plasticity in the CA2 region of the hippocampus. Pre-gestational maternal stress exposure resulted in significantly decreased rates of hippocampal neurogenesis and synaptophysin density in the dentate gyrus of pre-adolescent males, but not females. Together, these results further characterize the role of perinatal SSRIs, maternal stress prior to conception, and sex/gender on developing social behaviors and related plasticity in the hippocampus of pre-adolescent offspring. © 2017 Elsevier Lt