Fentanyl use has reached epidemic proportions, and more adults are administering the drug illicitly. Despite its high use rates, very little is known of the long-term effects following prenatal fentanyl exposure. Using an oral model of lower-dose prenatal fentanyl administration in mice, we found that fentanyl-exposed offspring developed similarly to their saline-exposed counterparts. In adulthood, there were few significant changes in tests of anxiety- and depression-like behavior, cognition, or ambulatory function. However, fentanyl-exposed mice, specifically males, exhibited significant deficits in social dominance and social interaction. RNA sequencing of the amygdala and subsequent examination of myelin basic protein levels suggested that prenatal fentanyl exposure affects myelin-related processes, which may impact the subsequent behavioral changes. These data suggest that in utero fentanyl exposure could significantly alter social-related behaviors, which may be related to aberrant brain myelination and connectivity.

L'évaluation des risques ou de la sécurité d'utilisation des médicaments chez la femme enceinte ou susceptible de le devenir est une mission importante de la pharmacovigilance. Ainsi, les centres régionaux de pharmacovigilance (CRPV) sont impliqués en tant que centres d'informations sur le médicament, afin d'apporter une évaluation personnalisée du risque et des conseils individualisés à l'occasion d'une grossesse, et doivent aussi assurer un suivi systématique de l'évolution des grossesses exposées dont ils ont eu connaissance. La nécessité d'une gestion harmonisée et commune de ces cas d'exposition, et la spécificité de cette problématique, ont conduit à la création d'une base de données dédiée. Terappel a ainsi été mis à la disposition des 19 CRPV qui en ont fait la demande. Les données prospectives de cette base sont utilisées par les centres pour des études collaboratives descriptives ou comparatives nationales, ou en participant à des projets initiés par l'European network of teratology information services (ENTIS), dans le but d'apporter des informations sur le profil de sécurité ou de toxicité d'une exposition médicamenteuse chez une femme enceinte. Les caractéristiques de cette base de données et des exemples d'utilisation sont présentés dans cet article.Risk assessment and recommendations regarding the use of medicines during pregnancy or in women of childbearing age is an important task of pharmacovigilance. As a drug information resource, the network of French regional pharmacovigilance centres is involved in providing a personalized risk assessment and individualized counselling during pregnancy. It must also ensure systematic follow-up of exposed pregnancies for which it has been contacted. To ensure harmonized data collection and followup, a dedicated database was set-up in 1984 by the Lyon pharmacovigilance centre, which was later made available to 18 other centres. Prospective data from this database is regularly used by the network for descriptive or comparative collaborative studies at the national level or by participating to studies initiated by the European Network of Teratology Information Services in order to provide information on the safety profile of drug exposure in pregnant women. The characteristics of this database and examples of utilization are described in this article.

The impact of sex on long-term outcomes after pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (PH) remains unclear. We therefore examined the early and long-term outcome after PEA to determine whether sex had an impact on the risk of residual PH and need for targeted PH medical therapy.Retrospective study of 401 consecutive patients undergoing PEA at our institution between August 2005 and March 2020 was performed. Primary outcome was the need for targeted PH medical therapy postoperatively. Secondary outcomes included survival and measures of hemodynamic improvement.Females (N = 203, 51%) were more likely to have preoperative home oxygen therapy (29.6% vs 11.6%, p < 0.01), and to present with segmental and subsegmental disease compared to males (49.2% vs 21.2%, p < 0.01). Despite similar preoperative values, females had higher postoperative pulmonary vascular resistance (final total pulmonary vascular resistance after PEA, 437 Dynes∙s∙cm−5 vs 324 Dynes∙s∙cm−5 in males, p < 0.01). Although survival at 10 years was not significantly different between sexes (73% in females vs 84% in males, p = 0.08), freedom from targeted PH medical therapy was lower in females (72.9% vs 89.9% in males at 5 years, p < 0.001). Female sex remained an independent factor affecting the need for targeted PH medical therapy after PEA in multivariate analysis (HR 2.03, 95%CI 1.03–3.98, p = 0.04).Although outcomes are excellent for both sexes, females had greater need for targeted PH medical therapy in the long-term. Early reassessment and long-term follow-up of these patients are important. Further investigations into possible mechanisms to explain the differences are warranted.

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

Evidence supporting the use of glucagon-like peptide-1 (GLP-1) analogues to pharmacologically treat disorders beyond type 2 diabetes and obesity is increasing. However, little is known about how activation of the GLP-1 receptor (GLP-1R) during pregnancy affects maternal and offspring outcomes. We treated female C57Bl/6 J mice prior to conception and throughout gestation with a long-lasting GLP-1R agonist, Exendin-4. While GLP-1R activation has significant effects on food and drug reward, depression, locomotor activity, and cognition in adults, we found few changes in these domains in exendin-4-exposed offspring. Repeated injections of Exendin-4 had minimal effects on the dams and may have enhanced maternal care. Offspring exposed to the drug weighed significantly more than their control counterparts during the preweaning period and demonstrated alterations in anxiety-like outcomes, which indicate a developmental role for GLP-1R modulation in the stress response that may be sex-specific.

The devastating impact of opioid abuse and dependence on the individual, family, and society are well known but extremely difficult to combat. During pregnancy, opioid drugs and withdrawal also affect fetal brain development and newborn neural functions, in addition to maternal effects. Neonatal Abstinence Syndrome/Neonatal Opioid Withdrawal Syndrome (NAS/NOWS) rates have drastically increased in the US in the past decade. Solutions to this complex problem must be multi-faceted, which would be greatly enhanced by a translational, multidisciplinary understanding. Therefore, this mini-review incorporates biomedical, clinical, and policy aspects of opioid use during pregnancy. We review the known roles for endogenous opioids in mediating circuit formation and function in the developing brain, discuss how exogenous opioid drug use and addiction impact these processes in animal models and humans, and discuss the implications of these data on public policy. We suggest that some current policy initiatives produce unintended harm on both mothers and their children and delineate recommendations for how legislation could better contribute to addiction recovery and increase neural resilience in affected children. Impact statement Opioid abuse is a critical epidemic affecting individuals, families, and communities. This mini-review summarizes current literature on the impact of opioid drugs-including prescription pain relievers and illicit opioids-on neurobiological and neurobehavioral development. Using concepts related to the medical model of addiction as a brain disease, we review the public policy implications of these data and identify needs for future investigations.

The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been purported to have antidepressant-like and cognitive-enhancing effects. Many people suffering from major depressive disorder (MDD) also experience deficits in cognition. While currently approved antidepressant pharmacotherapies can alleviate the mood symptoms in some patients, they do not treat the cognitive ones. We tested whether systemic administration of a GLP-1R agonist would alter location discrimination, a cognitive task that is diminished in humans with MDD. Male and female laboratory mice (6–8 weeks old, N = 6–14/sex) were trained in a touchscreen operant task of location discrimination. Upon reaching baseline criterion, mice were administered vehicle or a GLP-1R agonist, Exendin-4, systemically prior to testing in probe trials of varying difficulty. Following GLP-1R activation, males showed modest yet non-significant performance in the location discrimination task. Females, however, showed enhanced performance during the most difficult probe tests following Exendin-4 administration. GLP-1R activation appears to enhance overall performance in the location discrimination task and does so in a sex- and difficulty-dependent manner. These preliminary yet impactful data indicate that GLP-1R agonists may be useful as an adjunctive pharmacotherapy to treat cognitive deficits associated with MDD and/or multiple neurological disorders.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a number of functions to maintain energy homeostasis and contribute to motivated behavior, both peripherally and within the central nervous system (CNS). These functions, which include insulin secretion, gastric emptying, satiety, and the hedonic aspects of food and drug intake, are primarily mediated through stimulation of the GLP-1 receptor. While this receptor plays an important role in a variety of physiological outcomes, data regarding its CNS expression has been primarily limited to regional receptor binding and single-label transcript expression studies. We thus developed a bacterial artificial chromosome transgenic mouse, in which expression of a red fluorescent protein (mApple) is driven by the GLP-1R promoter. Using this reporter mouse, we characterized the regional and cellular expression patterns of GLP-1R expressing cells in the CNS, using double-label immunohistochemistry and in situ hybridization. GLP-1R-expressing cells were enriched in several key brain regions and circuits, including the lateral septum, hypothalamus, amygdala, bed nucleus of the stria terminalis, hippocampus, ventral midbrain, periaqueductal gray, and cerebral cortex. In most regions, GLP-1R primarily colocalized with GABAergic neurons, except within some regions such as the hippocampus, where it was co-expressed in glutamatergic neurons. GLP-1R-mApple cells were highly co-expressed with 5-HT3 receptor-containing neurons within the cortex and striatum, as well as with dopamine receptor- and calbindin-expressing cells within the lateral septum, the brain region in which GLP-1R is most highly expressed. In this manuscript, we provide detailed images of GLP-1R-mApple expression and distribution within the brain and characterization of these neurons.

Major Depressive Disorder (MDD) is a common mental illness that often produces cognitive impairments in patients, hindering affected individuals from performing daily life activities. In 2016, 16.2 million adults had at least one episode of major depression and at least half of these patients also experienced cognitive impairments (National Survey on Drug Use and Health). Current pharmacotherapies for MDD are somewhat effective at treating the symptoms related to affect but are not effective in treating the cognitive impairments associated with MDD. A propitious answer to an effective antidepressant pharmacotherapy for both of these symptoms is being sought in glucagon-like peptide-1 receptor (GLP1-R) agonists. Activation of this receptor plays a role in some types of learning and memory and increases hippocampal neurogenesis, a critical component of antidepressant efficacy. We utilized location discrimination and progressive ratio tasks in laboratory mice to investigate spatial learning and memory and motivation, respectively, hypothesizing that GLP-1R activation would enhance execution of these tasks. Our results demonstrate that GLP-1R activation enhances cognitive performance in the location discrimination task in a sex-dependent manner and negatively affects the motivation measured in the progressive ratio task. These data indicate that GLP-1R has potential to treat cognitive impairments associated with MDD, but its role in improving motivational and mood aspects of MDD requires further investigation. Support or Funding Information Funding provided by R03 MH110749 (DLG), R21DA035588 (GDS), and FSU CRC Planning Grant (DLG), and the FSU College of Medicine. Systemic Ex-4 treatment enhances performance in the LD probe trials (A). Ex-4-treated males performed better in the easy probe trial (B), while Ex-4-treated females performed better in the difficult probe trial (C). *p<0.05 vs. respective SAL, N=11–12/group In females, direct administration of Ex-4 into the brain (icv) did not alter performance in the easy probe LD trial (A), but did improve performance in the more difficult probe test (B). *p<0.001, N=4/group In both sexes, administration of Ex-4 systemically (ip) tended to decrease the number of trials performed in the PR test, suggesting reduced motivation, but statistical significance was not observed. N=8/group. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Depression is a multifactorial brain disorder caused by a variety of alterations in neural structure and function. We have used the Cre/loxP system to selectively delete dopamine D1 receptors from GABAergic neurons from the Nkx2.1 lineage within the medial ganglionic eminence (GABA‐D1‐cKO), which include a subset of crucial cerebral cortical interneurons within the frontal cortex. Cell‐type specific loss of D1 receptor expression was validated by in situ hybridization. Neurobehavioral analyses of GABA‐D1‐cKO mice revealed normal patterns of locomotor activity, anxiety, and spatial and nonspatial memory. However, GABA‐D1‐cKO mice exhibit decreased immobility in the forced swim test and decreased latency to consume a palatable liquid in a novel stressful environment; these are both indicative of an antidepressant‐like effect. GABA‐D1‐cKO mice also show reduced basal plasma corticosterone levels and down‐regulation of the neurexin Cntnap4 in cerebral cortical interneurons. Conditional deletion of dopamine D1 receptors from telencephalic glutamatergic neurons (using Emx1‐Cre as a deletor) does not induce these phenotypes. These data suggest a new mechanism by which cerebral cortical interneurons may contribute to mood regulation and identify a new potential mechanism to exploit in the treatment and prevention of this prevalent brain disorder. Support or Funding Information Supported by FSU College of Medicine and MH116429. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The developmental impact of opioid use during pregnancy is a subject of ongoing debate. Short-term neonatal outcomes, such as lower birth weight and neonatal abstinence syndrome, are the most well-recognized outcomes. However, knowledge gaps exist regarding longer-term neurocognitive and mental health outcomes. In this article, we summarize an expert panel discussion that was held in April 2018 by the Substance Abuse and Mental Health Services Administration and attended by national experts in the field of perinatal opioid exposure and its impact on child development. Despite the challenges with research in this area, there is emerging literature revealing an association between neonates exposed to opioids in utero and longer-term adverse neurocognitive, behavioral, and developmental outcomes. Although adverse sequalae may not be apparent in the neonatal period, they may become more salient as children develop and reach preschool and school age. Multiple variables (genetic, environmental, and biological) result in a highly complex picture. The next steps and strategies to support families impacted by opioid use disorder are explored. Model programs are also considered, including integrated care for the child and mother, parenting supports, and augmentations to home visiting.

Behavior is the final output of the nervous system, and alterations in behavior reflect changes in the underlying structure and function of the brain. Behavioral testing is a critical component of developmental neurotoxicity assessment. The primary aim of this chapter is to describe simple test approaches used in behavioral assessment within developmental neurotoxicology. We focus here on rodents, particularly rats and mice, which are the most commonly used animals in behavioral teratology. Current practice typically involves the examination of toxicant-exposed and control offspring for physical growth, attainment of physical developmental landmarks, sensory function, motor development, activity, and learning. Together, these measures encompass a broad range of basic processes, most of which can either be studied using rapid and simple manual techniques or have been adapted for automated assessment.

Neonatal exposure to methamphetamine (MA) and developmental chronic stress significantly alter neurodevelopmental profiles that show a variety of long-term physiological and behavioral effects. In the current experiment, Sprague-Dawley rats were exposed to one of two housing conditions along with MA. Rats were given 0 (saline), 5, or 7.5 mg/kg MA, four times per day from postnatal day (P)11 to 15 or P11 to 20. Half of the litters were reared in cages with standard bedding and half with no bedding. Separate litters were assessed at P15 or P20 for organ weights (adrenals, spleen, thymus); corticosterone; and monoamine assessments (dopamine, serotonin, norepinephrine) and their metabolites within the neostriatum, hippocampus, and prefrontal cortex. Findings show neonatal MA altered monoamines, corticosterone, and organ characteristics alone, and as a function of developmental age and stress compared with controls. These alterations may in part be responsible for MA and early life stress-induced long-term learning and memory deficits.