The effects of buprenorphine and morphine during pregnancy: Impact of exposure length on maternal brain, behavior, and offspring neurodevelopment.

The escalating incidence of opioid-related issues among pregnant women in the United States underscores the critical necessity to understand the effects of opioid use and Medication for Opioid Use Disorders (MOUDs) during pregnancy. This research employed a translational rodent model to examine the impact of gestational exposure to buprenorphine (BUP) or morphine on maternal behaviors and offspring well-being. Female rats received BUP or morphine before conception, representing established use, with exposure continuing until postnatal day 2 or discontinued on gestational day 19 to mimic treatment cessation before birth. Maternal behaviors - including care, pup retrieval, and preference - as well as hunting behaviors and brain neurotransmitter levels were assessed. Offspring were evaluated for mortality, weight, length, milk bands, surface righting latency, withdrawal symptoms, and brain neurotransmitter levels. Our results reveal that regardless of exposure length (i.e., continued or discontinued), BUP resulted in reduced maternal care in contrast to morphine-exposed and control dams. Opioid exposure altered brain monoamine levels in the dams and offspring, and was associated with increased neonatal mortality, reduced offspring weight, and elevated withdrawal symptoms compared to controls. These findings underscore BUP's potential disruption of maternal care, contributing to increased pup mortality and altered neurodevelopmental outcomes in the offspring. This study calls for more comprehensive research into prenatal BUP exposure effects on the maternal brain and infant development with the aim to mitigate adverse outcomes in humans exposed to opioids during pregnancy.

Maternal care behavior and physiology moderate offspring outcomes following gestational exposure to opioids.

The opioid epidemic has resulted in a drastic increase in gestational exposure to opioids. Opioid-dependent pregnant women are typically prescribed medications for opioid use disorders ("MOUD"; e.g., buprenorphine [BUP]) to mitigate the harmful effects of abused opioids. However, the consequences of exposure to synthetic opioids, particularly BUP, during gestation on fetal neurodevelopment and long-term outcomes are poorly understood. Further, despite the known adverse effects of opioids on maternal care, many preclinical and clinical studies investigating the effects of gestational opioid exposure on offspring outcomes fail to report on maternal care behaviors. Considering that offspring outcomes are heavily dependent upon the quality of maternal care, it is important to evaluate the effects of gestational opioid exposure in the context of the mother-infant dyad. This review compares offspring outcomes after prenatal opioid exposure and after reduced maternal care and integrates this information to potentially identify common underlying mechanisms. We explore whether adverse outcomes after gestational BUP exposure are due to direct effects of opioids in utero, deficits in maternal care, or a combination of both factors. Finally, suggestions for improving preclinical models of prenatal opioid exposure are provided to promote more translational studies that can help to improve clinical outcomes for opioid-dependent mothers.

Impact of prenatal cannabis exposure on functional connectivity of the salience network in children.

Cannabis use among pregnant people has increased over the past decade. This is of concern as prenatal cannabis exposure (PCE) is associated with cognitive, motor, and social deficits among offspring. Here, we examined resting-state functional connectivity (rsFC) of the salience network (SN)-a core neurocognitive network that integrates emotional and sensory information-in children with (vs. without) PCE. Using neuroimaging and developmental history data collected from 10,719 children (M ± SD = 9.92 ± 0.62 years; 47.9% female) from the Adolescent Brain Cognitive Development study, we assessed the impact of parent-reported PCE (before or after knowledge of pregnancy) on rsFC within and between the SN and five other core neurocognitive networks. We also evaluated whether SN rsFC mediated the association between PCE and child psychopathology. Results showed that PCE before (but not after) knowledge of pregnancy was associated with lower SN-ventral attention network (VAN) rsFC. Furthermore, psychotic-like experiences mediated the association between PCE and SN-VAN rsFC, and reversal of the model was also significant, such that SN-VAN rsFC mediated the association between PCE and psychotic-like symptoms. However, these mediation effects were no longer significant after the inclusion of covariates. Taken together, these findings suggest that developmental alterations in SN-VAN interactions may explain the previously reported association between PCE and elevated risk of child psychopathology.

Developmental Manipulation-Induced Changes in Cognitive Functioning.

Schizophrenia is a complex neurodevelopmental disorder with as-yet no identified cause. The use of animals has been critical to teasing apart the potential individual and intersecting roles of genetic and environmental risk factors in the development of schizophrenia. One way to recreate in animals the cognitive impairments seen in people with schizophrenia is to disrupt the prenatal or neonatal environment of laboratory rodent offspring. This approach can result in congruent perturbations in brain physiology, learning, memory, attention, and sensorimotor domains. Experimental designs utilizing such animal models have led to a greatly improved understanding of the biological mechanisms that could underlie the etiology and symptomology of schizophrenia, although there is still more to be discovered. The implementation of the Research and Domain Criterion (RDoC) has been critical in taking a more comprehensive approach to determining neural mechanisms underlying abnormal behavior in people with schizophrenia through its transdiagnostic approach toward targeting mechanisms rather than focusing on symptoms. Here, we describe several neurodevelopmental animal models of schizophrenia using an RDoC perspective approach. The implementation of animal models, combined with an RDoC framework, will bolster schizophrenia research leading to more targeted and likely effective therapeutic interventions resulting in better patient outcomes.

The effects of neonatal procedural pain and maternal isolation on hippocampal cell proliferation and reelin concentration in neonatal and adult male and female rats.

Preterm births accounted for over 10% of all U.S. live births in 2019 and the rate is rising. Neonatal stressors, especially procedural pain, experienced by preterm infants in the neonatal intensive care unit (NICU) have been associated with neurodevelopmental impairments. Parental care can alleviate stress during stressful or painful procedures; however, infants in the NICU often receive reduced parental care compared with their peers. Animal studies suggest that decreased maternal care similarly impairs neurodevelopment but also influences the effects of neonatal pain. It is important to mimic both stressors in animal models of neonatal stress exposure. In this study, researchers investigated the individual and combined impact of neonatal pain and maternal isolation on reelin protein levels and cellular proliferation in the hippocampal dentate gyrus of 8 days old and adult rats. Exposure to either stressor individually, but not both, increased reelin levels in the dentate gyrus of adult females without significantly altering reelin levels in adult males. However, cell proliferation levels at either age were unaffected by the early-life stressors. These results suggest that each early-life stressor has a unique effect on markers of brain development and more research is needed to further investigate their distinct influences.

Effects of fentanyl on acute locomotor activity, behavioral sensitization, and contextual reward in female and male rats.

BACKGROUND: Although fentanyl has gained widespread prominence, there remains a lack of knowledge on this opioid synthetic agonist, particularly related to sex effects. Therefore, we conducted behavioral tests in female and male rats to measure drug abuse-related responses to fentanyl hypothesizing sex-specific responses. METHODS: Using female and male rats, we measured the effects of acute or repeated administration of fentanyl (20 µg/kg) on locomotor activity (LMA) and behavioral sensitization in an open field test. We further measured contextual-reward and associated locomotor activity during training in a conditioned place preference (CPP) paradigm using a low (4 µg/kg) or high (16 µg/kg) dose of fentanyl. Vaginal lavage samples were collected from female rats in the CPP study, and the estrous phase was determined based on the cytological characterization. RESULTS: Female, but not male, rats showed elevated LMA in response to acute fentanyl and behavioral sensitization to repeated administration of fentanyl. Fentanyl produced significant CPP in both sexes, but it was more potent in males. Finally, our secondary investigation of the estrous cycle on fentanyl-CPP suggests that non-estrus phases, likely reflecting high estradiol, may predict the degree of fentanyl preference in females. CONCLUSIONS: Fentanyl was more potent and/or effective to produce LMA and LMA sensitization in females but more potent to produce CPP in males. Furthermore, the role of sex in fentanyl responses varied across endpoints, and sex differences in LMA were not predictive of sex differences in CPP.

Opioid use during pregnancy can impair maternal behavior and the Maternal Brain Network: A literature review.

Opioid Use Disorder (OUD) is a global epidemic also affecting women of reproductive age. A standard form of pharmacological treatment for OUD is Opioid Maintenance Therapy (OMT) and buprenorphine has emerged as the preferred treatment for pregnant women with OUD relative to methadone. However, the consequences of BUP exposure on the developing Maternal Brain Network and mother-infant dyad are not well understood. The maternal-infant bond is dependent on the Maternal Brain Network, which is responsible for the dynamic transition from a "nulliparous brain" to a "maternal brain". The Maternal Brain Network consists of regions implicated in maternal care (e.g., medial preoptic area, nucleus accumbens, ventral pallidum, ventral tegmentum area) and maternal defense (e.g., periaqueductal gray). The endogenous opioid system modulates many of the neurochemical changes in these areas during the transition to motherhood. Thus, it is not surprising that exogenous opioid exposure during pregnancy can be disruptive to the Maternal Brain Network. Though less drastic than misused opioids, OMTs may not be without risk of disrupting the neural and molecular structures of the Maternal Brain Network. This review describes the Maternal Brain Network as a framework for understanding how pharmacological differences in exogenous opioid exposure can disrupt the onset and maintenance of the maternal brain and summarizes opioid and OMT (in particular buprenorphine) use in the context of pregnancy and maternal behavior. This review also highlights future directions for evaluating exogenous opioid effects on the Maternal Brain Network in the hopes of raising awareness for the impact of the opioid crisis not only on exposed infants, but also on mothers and subsequent mother-infant bonds.

Probiotic treatment (Bifidobacterium longum subsp. longum 35624™) affects stress responsivity in male rats after chronic corticosterone exposure.

Mounting evidence suggests that gut microbiota do not only regulate intestinal function and health, but that they also play a role in mental health via the gut-brain axis. Previous research further suggests that probiotics may have beneficial health effects, but more research is needed to confirm these beneficial effects and better understand the underlying mechanisms and potential sex differences in the response to probiotics. Therefore, the current study investigates the effects of chronic administration of the commercially available probiotic Bifidobacterium longum subsp. longum 35624™(B. 35624) to male and female rats under control or "stressed" conditions. For this, 24 male and 24 female Sprague-Dawley rats were either given daily corticosterone injections (40 mg/kg; to induce depressive-like behavior and a "stressed" condition) or oil injections (controls) together with oral administration of B.35624 or vehicle for 21 days (n = 5-7/group). Animals performed the Open Field Test (OFT) and Forced Swim Test (FST) and several blood samples were collected to investigate basal as well as stress-induced corticosterone levels. Rats were sacrificed on day 22 and their brains sliced and stained with doublecortin, a marker of immature neurons. Results showed that B.35624 was not able to rescue depressive-like behavior or induce changes in neurogenesis in males or females, but the probiotic impacted hypothalamic-pituitary-adrenal axis functioning in male animals and tended to reduce anxiolytic behavior in the OFT. More research is needed to further elucidate the potential health effects of probiotics especially in regard to possible sex differences.

Neonatal pain and reduced maternal care alter adult behavior and hypothalamic-pituitary-adrenal axis reactivity in a sex-specific manner.

Preterm infants often spend a significant amount of time in the neonatal intensive care unit (NICU) where they are exposed to many stressors including pain and reduced maternal care. These early-life stressful experiences can have negative consequences on brain maturation during the neonatal period; however, less is known about the long-term cognitive and affective outcomes. Thus, this study was conducted to investigate the impact of neonatal pain and reduced maternal care on adult behavior and HPA axis reactivity in an animal model. Male and female rats underwent a series of repetitive needle pokes and/or reduced maternal care (through a novel tea ball infuser encapsulation method) during the first 4 days of life and were then assessed in a battery of behavioral tests as adults. We found that early-life pain enhanced spatial learning independent of the animal's sex, but altered HPA recovery from an acute stressor in females only. Moreover, reduced maternal care altered long-term spatial memory and reversal learning in males. These findings indicate that neonatal stressors have unique sex-dependent long-term biobehavioral effects in rodents. Continued examination of the behavioral consequences of these stressors may help explain varying vulnerability and resiliency in preterm infants who experienced early stress in the NICU.

Gestational buprenorphine exposure: Effects on pregnancy, development, neonatal opioid withdrawal syndrome, and behavior in a translational rodent model.

BACKGROUND: The opioid crisis has led to an increased number of pregnant opioid-dependent women receiving opioid-maintenance therapy (e.g. buprenorphine, BUP), but little is known about the consequences of gestational BUP exposure on pregnancy outcomes, maternal care, or offspring development. METHODS: Our translational rodent model began BUP exposure to adult female rats (N = 30) at least 7 days before conception and continued throughout the postpartum period. Both therapeutic low-dose (BUP-LD, 0.3 mg/kg, s.c.) and overexposure high-dose (BUP-HD, 1.0 mg/kg) doses of BUP were compared to saline control. Female rats were bred in house with drug-naïve adult male rats. The day after parturition, litters were culled to 5 males/5 females and assigned randomly to various behavioral tests and assessed either neonates or adolescents. Litter characteristics, maternal caregiving, Neonatal Opioid Withdrawal Syndrome (NOWS), offspring development and adolescent behaviors were evaluated. RESULTS: BUP-LD decreased maternal care, delayed offspring development, decreased offspring body weight, length, temperature, and pain sensitivity (p's < .05). BUP-HD drastically reduced maternal care and offspring survival, altered litter characteristics, and increased NOWS (p's < .05). CONCLUSION: These results demonstrate that the therapeutic BUP-LD in rats was relatively safe with subtle effects on maternal care and rodent offspring. However, overexposure BUP-HD in rats produced NOWS and compromised maternal caregiving as well as rodent offspring survival. More research is critical to validate the translational implication of these findings for human opioid-dependent mothers maintained on BUP-maintenance therapy.

Effects of opioids on the parental brain in health and disease.

The epidemic of opioid use disorder (OUD) directly affects millions of women of child-bearing age. Unfortunately, parenting behaviors - among the most important processes for human survival - are vulnerable to the effects of OUD. The standard of care for pregnant women with OUD is opioid maintenance therapy (OMT), of which the primary objective is to mitigate addiction-related stress. The aim of this review is to synthesize current information specific to pregnancy and parenting that may be affected by OUD. We first summarize a model of the parental brain supported by animal research and human neuroimaging. We then review animal models of exogenous opioid effects on parental brain and behavior. We also present preliminary data for a unifying hypothesis that may link different effects of exogenous opioids on parenting across species and in the context of OMT. Finally, we discuss future directions that may inform research and clinical decision making for peripartum women with OUD.

Developmental outcomes after gestational antidepressant treatment with sertraline and its discontinuation in an animal model of maternal depression.

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed to women before or during pregnancy to manage their depressive symptoms. However, there is still little knowledge regarding the long-term development effects of SSRI exposure for the fetus or the effects of discontinuing SSRI treatment during pregnancy. This study utilized a translational animal model of maternal depression (based on giving high levels of corticosterone (CORT, 40 mg/kg, s.c.) or vehicle (Oil) for 21 days prior to conception) to investigate the effects of sertraline (a frequently prescribed SSRI; 20 mg/kg p.o., treatment started ∼7 days prior to conception) and its discontinuation during pregnancy (on gestational day 16) compared to vehicle (water) treatment on the development of the offspring. Our results revealed that both corticosterone exposure prior to pregnancy and sertraline administration and its discontinuation during gestation had sex-specific effects on behavior in the adult offspring. In particular, pre-conceptional maternal corticosterone treatment impacted the stress response, anxiety-like behavior and cognitive performance in adult female offspring, while gestational SSRI exposure and its discontinuation compared to full-term exposure affected impulsivity in females, and exploratory behavior in males. More research is needed on the effects of exposure to antidepressant medication and its discontinuation compared to depression during pregnancy and how each impacts development to better help women make informed decisions about their medication use during pregnancy.

Trick or treat? Evaluating contributing factors and sex-differences for developmental effects of maternal depression and its treatment.

Maternal depression and treatment with selective serotonin reuptake inhibitors (SSRIs), the most common form of pharmaceutical intervention, can both have an impact on infant development. As such, it is difficult for healthcare providers to recommend a course of treatment to expectant mothers suffering from depression, or to women on antidepressant medication prior to pregnancy. This review will discuss the existing research on the developmental impacts of maternal depression and its treatment with SSRIs, with a particular focus on contributing factors that complicate our attempt to disentangle the consequences of maternal depression and its treatment such as the timing or severity of the depression. We will explore avenues for translational animal models to help address the question of "Trick or Treat", i.e.: which is worse for offspring development: exposure to maternal depression, or the SSRI treatment? Further, we will explore sex-dependent outcomes for the offspring in human and animal studies as male and female offspring may react differently to the presence of maternal depression or antidepressant treatment. Without more clinical and preclinical data, it remains difficult for women to make an informed decision regarding their depression treatment before, during, and after their pregnancy.

Resilience priming: Translational models for understanding resiliency and adaptation to early life adversity.

Despite the increasing attention to early life adversity and its long-term consequences on health, behavior, and the etiology of neurodevelopmental disorders, our understanding of the adaptations and interventions that promote resiliency and rescue against such insults are underexplored. Specifically, investigations of the perinatal period often focus on negative events/outcomes. In contrast, positive experiences (i.e. enrichment/parental care//healthy nutrition) favorably influence development of the nervous and endocrine systems. Moreover, some stressors result in adaptations and demonstrations of later-life resiliency. This review explores the underlying mechanisms of neuroplasticity that follow some of these early life experiences and translates them into ideas for interventions in pediatric settings. The emerging role of the gut microbiome in mediating stress susceptibility is also discussed. Since many negative outcomes of early experiences are known, it is time to identify mechanisms and mediators that promote resiliency against them. These range from enrichment, quality parental care, dietary interventions and those that target the gut microbiota.

Repetitive neonatal pain and reduced maternal care alter brain neurochemistry.

Preterm infants are exposed to many stressors while in the neonatal intensive care unit including pain and reduced maternal care. Both stressors can have a profound negative impact on brain development, and the present study sought to investigate some of the biological mechanisms underlying this phenomenon. Rat pups underwent a series of repetitive needle pokes and/or reduced maternal care through a novel tea-ball infuser encapsulation model during the first four days of life. On postnatal day four, pups were sacrificed and serum was analyzed for corticosterone, while brains were tested for various neurotransmitters and brain metabolites through magnetic resonance spectroscopy. We found that exposure to maternal isolation and neonatal pain produced an increase in serum corticosterone but decreased glutamate levels in the hippocampus and frontal cortex. These alterations in stress responding and neurochemistry in response to the early-life stressors may help explain some of the negative outcomes seen in preterm infants.

Neonatal pain and reduced maternal care: Early-life stressors interacting to impact brain and behavioral development.

Advances in neonatal intensive care units (NICUs) have drastically increased the survival chances of preterm infants. However, preterm infants are still exposed to a wide range of stressors during their stay in the NICU, which include painful procedures and reduced maternal contact. The activation of the hypothalamic-pituitary-adrenal (HPA) axis, in response to these stressors during this critical period of brain development, has been associated with many acute and long-term adverse biobehavioral outcomes. Recent research has shown that Kangaroo care, a non-pharmacological analgesic based on increased skin-to-skin contact between the neonate and the mother, negates the adverse outcomes associated with neonatal pain and reduced maternal care, however the biological mechanism remains widely unknown. This review summarizes findings from both human and rodent literature investigating neonatal pain and reduced maternal care independently, primarily focusing on the role of the HPA axis and biobehavioral outcomes. The physiological and positive outcomes of Kangaroo care will also be discussed in terms of how dampening of the HPA axis response to neonatal pain and increased maternal care may account for positive outcomes associated with Kangaroo care.

Parity modifies the effects of fluoxetine and corticosterone on behavior, stress reactivity, and hippocampal neurogenesis.

The postpartum confers considerable risk for developing depression. Depressed patients have elevated cortisol concentrations and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback. Chronic stress or corticosterone (CORT) induces a depressive-like phenotype in rodents, including during the postpartum. The present study examined whether nulliparous and postpartum rats were differentially vulnerable to chronic high CORT and whether fluoxetine (FLX) would differentially alter the brain, behavior, and neuroendocrine function depending on reproductive experience. Nulliparous and postpartum female Sprague-Dawley rats were divided into 4 groups that received 21 d of injections of CORT or oil plus FLX or saline. CORT reduced maternal behaviors whereas FLX reversed CORT-induced decreases in maternal care. CORT increased immobility in the forced swim test (FST), but FLX did not significantly alter immobility in either nulliparous or postpartum rats. Dams spent less time immobile and had lower CORT concentrations after the FST compared with nulliparae, indicating that aspects of the postpartum period may provide resilience against a depressive-like phenotype. Both CORT and parity reduced neurogenesis (doublecortin expression) in the dentate gyrus. FLX-treated rats had lower CORT concentrations following the FST and more immature neurons, but only in the nulliparous, and not postpartum, groups. These data suggest that the postpartum may inherently protect against some deleterious effects of high CORT but also confer resistance to the neurogenic and endocrine effects of FLX. Our findings are important for understanding how females in different reproductive states respond to glucocorticoids and antidepressants.

Postpartum depression: Etiology, treatment and consequences for maternal care.

This article is part of a Special Issue "Parental Care". Pregnancy and postpartum are associated with dramatic alterations in steroid and peptide hormones which alter the mothers' hypothalamic pituitary adrenal (HPA) and hypothalamic pituitary gonadal (HPG) axes. Dysregulations in these endocrine axes are related to mood disorders and as such it should not come as a major surprise that pregnancy and the postpartum period can have profound effects on maternal mood. Indeed, pregnancy and postpartum are associated with an increased risk for developing depressive symptoms in women. Postpartum depression affects approximately 10-15% of women and impairs mother-infant interactions that in turn are important for child development. Maternal attachment, sensitivity and parenting style are essential for a healthy maturation of an infant's social, cognitive and behavioral skills and depressed mothers often display less attachment, sensitivity and more harsh or disrupted parenting behaviors, which may contribute to reports of adverse child outcomes in children of depressed mothers. Here we review, in honor of the "father of motherhood", Jay Rosenblatt, the literature on postnatal depression in the mother and its effect on mother-infant interactions. We will cover clinical and pre-clinical findings highlighting putative neurobiological mechanisms underlying postpartum depression and how they relate to maternal behaviors and infant outcome. We also review animal models that investigate the neurobiology of maternal mood and disrupted maternal care. In particular, we discuss the implications of endogenous and exogenous manipulations of glucocorticoids on maternal care and mood. Lastly we discuss interventions during gestation and postpartum that may improve maternal symptoms and behavior and thus may alter developmental outcome of the offspring.