Prenatal and postnatal bisphenol A exposure and social impairment in 4-year-old children.

BACKGROUND: Prenatal and postnatal exposure to bisphenol A (BPA) may affect early brain development. Rodent studies suggest that prenatal and postnatal neurodevelopmental toxicity from BPA exposure may manifest as social deficits in offspring. We investigated the association between prenatal and postnatal exposure to BPA and social impairments in a sample of 4-year-old children. METHODS: We recruited second-trimester pregnant women between 2008 and 2011, and measured their creatinine-adjusted prenatal urine BPA levels. In 2014-2015, a subset of 4-year-old children born to these women underwent neurobehavioral assessment and physical examination. We collected urine and blood from the children and assessed social impairments, including deficits in social interaction, social communication, and other behavior patterns using the Korean version of the Social Communication Questionnaire (K-SCQ) (n = 304). We examined social impairments associated with prenatal exposure at mid-term pregnancy and postnatal exposure to BPA at 4 years of age, using linear and piecewise linear regression models. RESULTS: The relationship between prenatal BPA exposure and social communication was non-linear and statistically significant at or above the flexion point for BPA levels of 3.0 µg/g creatinine in girls (58.4%, 95% confidence interval [CI], 6.5% to 135.8%). Each 2-fold increase in postnatal BPA exposure was significantly associated with an 11.8% (95% CI, 0.6% to 24.3%) increase in impairment in social communication in 4-year old girls, as indicated by the linear regression model. CONCLUSION: Prenatal and postnatal BPA exposure is associated with social impairment at 4 years of age, particularly in girls.

Maternal Immune Activation Disrupts Dopamine System in the Offspring.

BACKGROUND: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia. METHODS: Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology. RESULTS: Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity. CONCLUSIONS: These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.

Methamphetamine-induced deficits in social interaction are not observed following abstinence from single or repeated exposures.

The purpose of the current study was to assess social interaction (SI) following acute and repeated methamphetamine (MA) administration. Rats were injected with 5.0 mg/kg of MA and SI was tested 30 min or 24 h later. In another group of animals, MA sensitization was induced using 5.0 mg/kg of MA, and SI was assessed after 1 or 30 days of abstinence. SI was reduced in rats injected with MA 30 min, but not 24 h, before testing, compared with saline controls. Impaired SI was observed in combination with active avoidance of the conspecific animal. Repeated injections of MA progressively reduced locomotor activity and increased stereotypy, indicating that animals were sensitized. However, no differences in SI were observed 24 h or 30 days following the induction of sensitization. The absence of detectable differences in SI following MA sensitization may be attributable to the relatively short regimen used to induce sensitization. However, the current series of experiments provides evidence that an acute injection of MA decreases SI and simultaneously increases avoidance behavior, which supports a link between psychostimulant use and impaired social functioning. These data suggest that the acute injection model may provide a useful model to explore the neural basis of impaired social functioning and antisocial behavior.

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats.

Autism is a severe neurodevelopmental disorder characterized by qualitative impairments in social behavior, communication, and aberrant repetitive behaviors. A major focus of animal models of autism has been to mimic the social deficits of the disorder. The present study assessed whether rats exposed prenatally to valproic acid (VPA) show deficits in social play as juveniles that are consistent with the social deficits observed in autism. Dams were exposed to an acute dose of VPA on gestational day 12.5. Later, the playful interactions and associated ultrasonic vocalizations of the juveniles were examined. It was predicted that VPA-treated rats should play less than the controls. Characteristic of neurobehavioral insult at this early age, the VPA-treated juveniles showed significant increases in the frequency of body shakes and sexual mounting, but played at the same frequency as the controls. However, when playing, they were less likely to use tactics that facilitated bodily contact and vocalized less. These data suggest that prenatal VPA exposure disrupts some aspects of being able to communicate effectively and engage partners in dynamic interactions - deficits that are consistent with those observed in autism.

Improvement of ketamine-induced social withdrawal in rats: the role of 5-HT7 receptors.

Social withdrawal, one of the core negative symptoms of schizophrenia, can be modelled in the social interaction (SI) test in rats using N-methyl-D-aspartate receptor glutamate receptor antagonists. We have recently shown that amisulpride, an antipsychotic with a high affinity for serotonin 5-HT7 receptors, reversed ketamine-induced SI deficits in rats. The aim of the present study was to further elucidate the potential involvement of 5-HT7 receptors in the prosocial action of amisulpride. Acute administration of amisulpride (3 mg/kg) and SB-269970 (1 mg/kg), a 5-HT7 receptor antagonist, reversed ketamine-induced social withdrawal, whereas sulpiride (20 or 30 mg/kg) and haloperidol (0.2 mg/kg) were ineffective. The 5-HT7 receptor agonist AS19 (10 mg/kg) abolished the prosocial efficacy of amisulpride (3 mg/kg). The coadministration of an inactive dose of SB-269970 (0.2 mg/kg) showed the prosocial effects of inactive doses of amisulpride (1 mg/kg) and sulpiride (20 mg/kg). The anxiolytic chlordiazepoxide (2.5 mg/kg) and the antidepressant fluoxetine (2.5 mg/kg) were ineffective in reversing ketamine-induced SI deficits. The present study suggests that the antagonism of 5-HT7 receptors may contribute towards the mechanisms underlying the prosocial action of amisulpride. These results may have therapeutic implications for the treatment of negative symptoms in schizophrenia and other disorders characterized by social withdrawal.

(-)Epigallocatechin-3-gallate prevents the reserpine-induced impairment of short-term social memory in rats.

Reserpine has been confirmed to induce cognitive dysfunction and increase brain neural oxidative stress. Green tea catechins, particularly (-)epigallocatechin-3-gallate (EGCG), have strong antioxidative properties and can protect against numerous oxidative damages. In this study, we examined the possible protective effects of EGCG on reserpine-induced impairment of short-term memory in rats. Reserpine (1 mg/kg, intraperitoneal)-induced memory impairment was assessed using the social recognition task method; locomotor activity and the olfactory discrimination ability were not altered as measured by an open-field test and an olfactory discrimination test, respectively. EGCG treatment (100 and 300 mg/kg, intraperitoneal, for 7 days, starting 6 days before the reserpine injection) could improve the worsened social memory of reserpine-treated rats. Also, EGCG treatment reduced reserpine-induced lipid peroxidation and enhanced the antioxidation power in the hippocampi of reserpine-treated rats. These results suggest a protective effect of EGCG in treating reserpine-induced impairment of memory, most probably through its powerful antioxidative activities. Accordingly, EGCG may hold a clinically relevant value in preventing reserpine-induced cognitive dysfunction.

[Oxytocin: evidence for a therapeutic potential of the social neuromodulator]. / Oxytozin: Evidenz für ein therapeutisches Potenzial des sozialen Neuromodulators.

Only few substances have achieved such a great prominence in recent years as the hypothalamic neuropeptide oxytocin, which is also widely known as the love hormone. Oxytocin is a potent neuromodulator which can improve social cognitive functions including empathy, trust, cooperation and social learning. However, oxytocin can also promote negative social behavior and increase poor memory and feelings of fear in social situations. Positive data from initial clinical trials give rise to the hope that oxytocin will prove to be a substance which is suitable for targeted treatment of poor social-cognitive behavior in neuropsychiatric diseases. This review article summarizes the most important recent preclinical and clinical human studies and discusses the findings presented with respect to current concepts of personal and contextual influences.

Decision-making in Parkinson's disease patients with and without pathological gambling.

BACKGROUND AND PURPOSE: Pathological gambling (PG) in Parkinson's disease (PD) is a frequent impulse control disorder associated mainly with dopamine replacement therapy. As impairments in decision-making were described independently in PG and PD, the objective of this study was to assess decision-making processes in PD patients with and without PG. METHODS: Seven PD patients with PG and 13 age, sex, education and disease severity matched PD patients without gambling behavior were enrolled in the study. All patients were assessed with a comprehensive neuropsychiatric and cognitive evaluation, including tasks used to assess decision-making abilities under ambiguous or risky situations, like the Iowa Gambling Task (IGT), the Game of Dice Task and the Investment Task. RESULTS: Compared to PD patients without gambling behavior, those with PG obtained poorer scores in the IGT and in a rating scale of social behavior, but not in other decision-making and cognitive tasks. CONCLUSIONS: Low performance in decision-making under ambiguity and abnormal social behavior distinguished PD patients with PG from those without this disorder. Dopamine replacement therapy may induce dysfunction of the ventromedial prefrontal cortex and amygdala-ventral striatum system, thus increasing the risk for developing PG.

Prenatal valproate in rodents as a tool to understand the neural underpinnings of social dysfunctions in autism spectrum disorder.

Impairments in social interaction and verbal and non verbal communication are among the main features of Autism Spectrum Disorder (ASD). The causes of ASD are still unknown but the research efforts of the last decade have identified a number of factors (rare gene mutations, gene variations and adverse environmental events) that, interacting in complex ways, affect early brain development. The clinical evidence that prenatal exposure to the antiepileptic drug valproate (VPA) is associated with increased risk of neurodevelopmental delay, cognitive deficits and autism in children, has drawn the attention of scientists on VPA as a tool to unravel the environment contribution to ASD risk in children. In agreement with the clinical evidence, rodents prenatally exposed to VPA display behavioral anomalies resembling ASD symptoms. The mechanisms by which administration of VPA in pregnancy increases the risk of autism are still far to be clear as are still undetermined the specific targets of VPA in the developing brain both in humans and rodents. However, the robustness of the behavioral alterations, mainly in the social domain, and the neural/molecular changes revealed so far support the VPA model as a reliable instrument to investigate the neural underpinnings of social impairment. Here we provide an update of preclinical studies on prenatal exposure to VPA in rodents with a focus on the social and communication deficits induced by VPA, discussing potential pitfalls and future directions in this research field and corroborating the potential of the VPA model to identify new pharmacological targets for ASD. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.

Improvement of phencyclidine-induced social behaviour deficits in rats: involvement of 5-HT1A receptors.

We have recently shown that sub-chronic phencyclidine (PCP) treatment produces social behaviour deficits in female rats which are reversed by ziprasidone but not haloperidol or clozapine. This investigation was designed to extend the previous findings and identify the role of 5-HT(1A) receptors in mediating the effects of these drugs in this model. Female hooded-Lister rats received vehicle (n=36; intraperitoneal (i.p.)) or PCP (n=22; 2mg/kg, i.p.) twice daily for 7 days, followed by a 7-day washout period. On test days, PCP-treated rats were treated acutely with aripiprazole (5mg/kg, s.c.) or WAY100635 (0.5mg/kg, i.p.) alone and in combination. In a second experiment, PCP-treated rats were treated acutely with either fluoxetine (2.5mg/kg, i.p.) or chlordiazepoxide (CDP) (2.5mg/kg, i.p.) all 30 min prior to testing. For the test, pairs of unfamiliar rats receiving acute doses of drugs described above were placed in the test arena and social behaviours (following, sniffing, climbing over and under, exploration of inanimate object and avoiding) were recorded on video for subsequent blind scoring. The results showed that PCP-induced deficits in social behaviours were reversed by acute treatment with both aripiprazole and fluoxetine but not CDP or WAY100635. Furthermore, pre-treatment with WAY100635 prevented the reversal of social behaviour deficits observed with aripiprazole. These findings suggest that the beneficial effects of drugs such as aripiprazole and fluoxetine on PCP-induced social behaviour deficits, a potential model of negative symptoms of schizophrenia, may be a consequence of modifications of the serotonergic system, in particular through an interaction with 5-HT(1A) receptors.

Efficacy of antipsychotics to reverse phencyclidine-induced social interaction deficits in female rats--a preliminary investigation.

Sub-chronic phencyclidine (PCP) treatment mimics certain aspects of schizophrenia symptomology in rats. However, there is a marked lack of attempts to model negative symptomology such as social behaviour deficits in female rats. This study was conducted to assess whether sub-chronic PCP treatment produces social interaction deficits in female rats and to ascertain if these deficits can be reversed by either typical (haloperidol) or atypical (clozapine and ziprasidone) antipsychotics.

Further studies in the developmental hyperserotonemia model (DHS) of autism: social, behavioral and peptide changes.

Prior research has reliably found high blood (hyperserotonemia) - but low brain - serotonin levels in autistic individuals. At early stages of development, high levels of serotonin in the blood may enter the brain of a developing fetus, causing a loss of serotonin terminals through negative feedback and thus disrupting subsequent serotonergic function. The current study extends earlier findings in a developmental hyperserotonemia (DHS) model of autism in Sprague-Dawley rats by treating 8 dams of developing rat pups with a serotonergic agonist, 5-methoxytryptamine (5-MT; 1 mg/kg) during development (from gestational day 12 to post-natal day 20; PND 20). DHS pups exhibited post-injection seizures, which were non-existent in saline-treated pups (p<0.05). Behavioral results in infancy indicated that DHS pups spent less time with the dam during the active phase on PNDs 15-17 (p<0.05) and experienced decreased maternal bonding in a return to dam task on PND 17 (p<0.05). On subsequent tests, DHS animals exhibited greater gnawing reactions to a novel stimulus (p<0.05), less behavioral inhibition (p<0.05), and had fewer olfactory-based social interactions (p<0.05) and greater non-olfactory mounting (p<0.05). However, there were no changes in anxiogenic behavior using the elevated plus maze (p>0.05). Post mortem analyses revealed that DHS animals had a loss of oxytocin (OT)-containing cells in the paraventricular nucleus in the hypothalamus (PVN; p<0.05) as well as an increase in calcitonin-gene related peptide (CGRP; p<0.05, one tailed) processes in the central nucleus of the amygdala (CeA) on PND 198. These results may correspond to hypothalamic and amygdalar changes in the human condition and suggest that the hyperserotonemia model of autism may be a valid model which produces many of the social, behavioral, and peptide changes inherent to autism.

The putative antipsychotic alstonine reverses social interaction withdrawal in mice.

Negative symptoms of schizophrenia are particularly problematic due to their deleterious impact on a patient's social life. The indol alkaloid alstonine, the major component of traditional remedies used for treating mental illnesses in Nigeria, presents a clear antipsychotic-like profile in mice, as well as anxiolytic properties. Considering that social interaction is the core of negative symptoms, and that anxiolytic drugs can improve social interaction behavior, the aim of this study was to evaluate the effects of alstonine in the social interaction and MK801-induced social withdrawal models in mice. Sub-chronic (but not acute) treatment with alstonine 0.5 mg/kg (but not 1.0 mg/kg) significantly increased social interaction in mice. Moreover, MK801-induced social withdrawal was completely prevented by sulpiride (10 mg/kg) and alstonine 1.0 mg/kg, and partially prevented by alstonine 0.5 mg/kg. The study indicates that alstonine not only increases social interaction in normal mice, but also averts social deficits attributable to negative symptoms of schizophrenia. This study reinforces and complements the antipsychotic-like profile of alstonine, and emphasizes its potential as a drug useful for the management of negative symptoms in schizophrenia.

Social cognitive determinants of ecstasy use to target in evidence-based interventions: a meta-analytical review.

AIMS: The health hazards and prevalence of ecstasy use have been documented in two decades of research, but no review reporting on potentially modifiable antecedents of use is available. The aim of this study was to integrate systematically research identifying cognitive correlates of ecstasy use. Such research has the potential to identify targets for evidence-based interventions designed to discourage use. METHODS: The databases PsycINFO and MedLine were searched, inclusion criteria applied to resulting hits, and descendency and ancestry approaches applied to the selected publications. Reported associations between cognitive determinants, including intention to use and ecstasy use measures, were synthesized by calculating a weighted mean effect size, r. RESULTS: The pattern of associations lent support both to the theory of planned behaviour (TPB) and the expectancy approach as descriptions of potentially useful determinants. Attitudes were associated most strongly with intention and use, followed by subjective norm and perceived behavioural control. CONCLUSIONS: Consideration of the strength of associations and the potential modifiability of identified cognitions suggests that evidence-based interventions to discourage ecstasy use should target negative expectancies, perceived behavioural control and anticipated regret, and consider tailoring perceived behavioural control elements.

Taurine modulates acute ethanol-induced social behavioral deficits and fear responses in adult zebrafish.

Ethanol (EtOH) is a central nervous system (CNS) depressant drug that modifies various behavioral domains (i.e., sociability, aggressiveness, and memory) by promoting disinhibition of punished operant behavior and neurochemical changes. Taurine (TAU) is a ß-amino sulfonic acid with pleiotropic roles in the brain. Although exogenous TAU is found in energy drinks and often mixed with alcohol in beverages, the putative risks of mixing TAU and EtOH are poorly explored. Here, we investigated whether TAU modulates social and fear responses by assessing shoaling behavior, preference for conspecifics, and antipredatory behavior of adult zebrafish acutely exposed to EtOH. Zebrafish shoals (4 fish per shoal) were exposed to water (control), TAU (42, 150, and 400 mg/L), 0.25% (v/v) EtOH alone or in association with TAU for 1 h, and their behaviors were analyzed at different time intervals (0-5 min, 30-35 min, and 55-60 min). The effects of TAU and EtOH were further tested in a social preference test and during exposure to a predator. Both EtOH and TAU co-treated fish showed a higher shoal dispersion, while TAU 400/EtOH group shoal area had a similar profile when compared to control. However, in the social preference test, TAU 400/EtOH impaired the seeking for conspecifics. Regarding fear-like behaviors, TAU-cotreated fish showed a prominent reduction in risk assessments when compared to EtOH alone. Overall, we demonstrate that TAU modulates EtOH-induced changes in different behavioral domains, suggesting a complex relationship between social and fear-like responses.

The impact of diet on anti-social, violent and criminal behaviour.

The role of diet in anti-social behaviour was considered, paying particular attention to double-blind placebo-controlled trials. Meta-analysis of five well-designed studies found that elimination diets reduced hyperactivity-related symptoms, producing a summary standardized mean difference (SSMD) of 0.80 (95% CI 0.41-1.19). The picture was of children potentially responding to a wide range of food items although the pattern was individual to the child. Supplementation with poly-unsaturated fatty acids decreased violence (SSMD -0.61, 95% CI -0.83 to -0.39) although there was no evidence of an influence on hyperactivity. Three well-designed studies have reported that vitamin/mineral supplementation reduced anti-social behaviour. There are also findings of an association between a tendency to develop low blood glucose and aggression. Many responses to diet were idiosyncratic and involved a wide range of foods interacting with individual differences in physiology. Reactions were not observed in all members of groups chosen because they share a common behavioural designation or diagnosis.

Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders.

The gastrin-releasing peptide receptor (GRPR) has been implicated in central nervous system (CNS) diseases, including neurodevelopmental disorders associated with autism. In the present study we examined the effects of GRPR blockade during the neonatal period on behavioral measures relevant to animal models of neurodevelopmental disorders. Male Wistar rats were given an intraperitoneal (i.p.) injection of either saline (SAL) or the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095; 1 or 10mg/kg) twice daily for 10days from postnatal days (PN) 1 to 10. Animals treated with RC-3095 showed pronounced deficits in social interaction when tested at PN 30-35 and impaired 24-h retention of memory for both novel object recognition (NOR) and inhibitory avoidance (IA) tasks tested at PN 60-71. Neither short-term memory tested 1.5h posttraining nor open field behavior were affected by neonatal GRPR blockade. The implications of the findings for animal models of neurodevelopmental disorders are discussed.

From anxiety to autism: spectrum of abnormal social behaviors modeled by progressive disruption of inhibitory neuronal function in the basolateral amygdala in Wistar rats.

RATIONALE: Social behaviors are disrupted in several psychiatric disorders. The amygdala is a key brain region involved in social behaviors, and amygdala pathology has been implicated in disease states ranging from social anxiety disorder to autism. OBJECTIVE: To test the effects of progressive disruption of the inhibitory function within the basolateral nucleus of the amygdala (BLA) on conspecific social interaction in rats and investigate functional networks from the ventral medial prefrontal cortex (mPFCv) to the BLA. MATERIALS AND METHODS: BLA inhibitory tone was disrupted by priming it with the stress-peptide corticotrophin releasing factor (CRF) receptor agonist urocortin 1 (Ucn 1, 6 fmol), or by selective lesioning of a subset of BLA-GABAergic interneurons containing neurokinin 1 receptors using the targeted toxin SSP-Saporin. The effects of the disruption of GABAergic tone in the BLA were examined using a repeated exposure and habituation paradigm of social interaction (SI/h). Lesions and selectivity of lesions were confirmed postmortem. Additionally, effects of stimulating mPFCv on cFos activity in interneurons of the BLA were examined. RESULTS: Rats primed with Ucn 1 showed persistent social inhibition, which could be overcome with habituation, putatively modeling social anxiety. Rats with a selective lesioning of a subset of GABAergic interneurons in the BLA exhibited persistent social inhibition that was not reversed by SI/h paradigm. We also demonstrate selective functional inputs to this subset of interneurons when mPFCv was activated. CONCLUSIONS: These models with different gradations of disrupted BLA inhibition could help to study social dysfunction in disorders ranging from social anxiety to autism spectrum disorders.

Carbon monoxide incompletely prevents isoflurane-induced defects in murine neurodevelopment.

BACKGROUND: Commonly used anesthetics have been shown to disrupt neurodevelopment in preclinical models. It has been proposed that such anesthesia-induced neurotoxicity is mediated by apoptotic neurodegeneration in the immature brain. Low dose carbon monoxide (CO) exerts cytoprotective properties and we have previously demonstrated that CO inhibits isoflurane-induced apoptosis in the developing murine brain. Here we utilized anti-apoptotic concentrations of CO to delineate the role of apoptotic neurodegeneration in anesthesia-induced neurotoxicity by assessing the effect of CO on isoflurane-induced defects in neurodevelopment. METHODS: C57Bl/6 mouse pups underwent 1-hour exposure to 0ppm (air), 5ppm, or 100ppm CO in air with or without isoflurane on postnatal day 7. Cohorts were evaluated 5-7weeks post exposure with T-maze cognitive testing followed by social behavior assessment. Brain size, whole brain cellular content, and neuronal density in primary somatosensory cortex and hippocampal CA3 region were measured as secondary outcomes 1-week or 5-7weeks post exposure along with 7-day old, unexposed controls. RESULTS: Isoflurane impaired memory acquisition and resulted in abnormal social behavior. Low concentration CO abrogated anesthetic-induced defects in memory acquisition, however, it also resulted in impaired spatial reference memory and social behavior abnormalities. Changes in brain size, cellular content, and neuronal density over time related to the age of the animal and were unaffected by either isoflurane or CO. CONCLUSIONS: Anti-apoptotic concentrations of CO incompletely prevented isoflurane-induced defects in neurodevelopment, lacked concentration-dependent effects, and only provided protection in certain domains suggesting that anesthesia-related neurotoxicity is not solely mediated by activation of the mitochondrial apoptosis pathway.