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Single prolonged stress (SPS) is an experimental model that recapitulates in rodents some of the core symptoms of post-traumatic stress disorder (PTSD). Although women have a two-fold greater risk to develop PTSD, most preclinical studies have been carried out in males. Furthermore, the long-term effects of behavioral alterations induced by SPS have been rarely investigated. Here, we evaluated the long-term effects of SPS on PTSD-relevant behavioral domains in rats and whether these effects were sex-dependent. To this aim, separate cohorts of male and female adult rats were subjected to SPS and, 30 days later, long-term effects were assessed. We found that SPS exposure reduced locomotor activity in both sexes in an open field task. Males only showed increased anxiety-like behavior in the elevated plus maze and marble burying tests, enhanced acoustic startle response and impaired spatial memory retention while females were unaffected. SPS exposure did not alter auditory fear memory dynamics in males, but it did alter extinction retrieval in females. We provide the first evidence that SPS reproduces long-term emotional alterations in male, but not in female, rats which were observed 30 days following trauma exposure, thus resembling some of the hallmark symptoms of PTSD. Furthermore, our results show for the first time a long-term SPS-induced alteration of cued fear extinction in females. Our findings are relevant to future research on trauma-related disorders and may help develop sex-specific interventions to treat PTSD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Polyunsaturated long-chain omega-3 fatty acids (n3-PUFAs) are crucially involved in brain development and function. Inadequate n3-PUFA intake in rats during the perinatal period leads to behavioral deficits in adulthood, but early behavioral changes have not yet been investigated. The present study aimed to investigate potential behavioral alterations in neonatal rats exposed to a perinatal n3-PUFA imbalance. Female Sprague Dawley rats were fed an n3-PUFA-enriched or an n3-PUFA-deficient diet throughout mating, pregnancy, and lactation. Controls were fed an n6/n3-PUFA-balanced diet. We observed maternal behavior from postnatal day (PND) 2 to PND 13 and tested pups in the isolation-induced ultrasonic vocalization (USV) emission task at PNDs 3, 5, 9 and 13 to evaluate the impact of perinatal n3-PUFA on early emotional traits. Both the n3-PUFA-enriched and n3-PUFA-deficient diets profoundly decreased maternal behavior. At PNDs 3 and PND 5, pups of the n3-PUFA-deficient or -enriched diet groups emitted significantly fewer USVs compared with control pups. Further, the sonographic pattern of the USVs was altered in the test pups compared with the control pups at PND 9 and PND 13. The present findings indicate that both n3-PUFA deficiency and supplementation induce alterations in mother-infant interaction and early behavioral disturbances in the offspring., Competing Interests: Declaration of Competing Interest The authors declare that, except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity over the past five years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: Marijuana is the illicit drug most commonly used among pregnant and breastfeeding women. Different studies reported long-term adverse effects induced by in utero exposure to the main component of marijuana, Δ 9 -tetrahydrocannabinol (THC), both in rodents and in humans. However, little is known about any potential sex-dependent effects of marijuana consumption during pregnancy on newborns at early developmental ages., Experimental Approach: We studied the effects of prenatal exposure to the cannabinoid receptor agonist WIN55,212-2 (WIN; 0.5 mg·kg -1 from GD5 to GD20) on the emotional reactivity and cognitive performance of male and female rat offspring from infancy through adolescence and tested the role of mGlu 5 receptor signalling in the observed effects., Key Results: Prenatally WIN-exposed male infant pups emitted less isolation-induced ultrasonic vocalizations compared with male control pups, when separated from the dam and siblings and showed increased locomotor activity while females were spared. These effects were normalized when male pups were treated with the positive allosteric modulator of mGlu 5 receptor CDPPB. When tested at the prepubertal and pubertal periods, WIN-prenatally exposed rats of both sexes did not show any difference in social play behaviour, anxiety and temporal order memory., Conclusions and Implications: We reveal a previously undisclosed sexual divergence in the consequences of fetal cannabinoids on newborns at early developmental ages, which is dependent on mGlu 5 receptor signalling. These results provide new impetus for the urgent need to investigate the functional and behavioural substrates of prenatal cannabinoid exposure in both the male offspring and the female offspring., (© 2019 The British Pharmacological Society.)

Social play behaviour is a vigorous form of social interaction, abundant during the juvenile and adolescent phases of life in many mammalian species, including humans. Social play is highly rewarding and it is important for social and cognitive development. Being a rewarding activity, social play can be dissociated in its pleasurable and motivational components. We have previously shown that endocannabinoids modulate the expression of social play behaviour in rats. In the present study, we investigated whether endocannabinoids modulate the motivational and pleasurable properties of social play behaviour, using operant and place conditioning paradigms, respectively. Treatment with the anandamide hydrolysis inhibitor URB597 did not affect operant responding or social play-induced conditioned place preference (CPP) when administered at a dose (0.1mg/kg) known to increase the expression of social play behaviour, while it modestly reduced operant responding at a higher dose (0.2mg/kg). The cannabinoid-1 (CB1) receptor antagonist rimonabant reduced operant responding when administered at a dose (1mg/kg) known to decrease the expression of social play behaviour, although this effect may be secondary to concurrent drug-induced stereotypic behaviours (i.e., grooming and scratching). These data demonstrate that enhancing endocannabinoid levels does not differentially affect the motivational and pleasurable aspects of social play behaviour, whereas CB1 receptor blockade reduces the motivational aspects of social play behaviour, possibly due to response competition. Thus, endocannabinoids likely drive the expression of social play behaviour as a whole, without differentially affecting its motivational or pleasurable properties., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Our study is the first investigation of the effects of advanced paternal age (APA) on the developmental trajectory of social behavior in rodent offspring. Given the strong epidemiological association between APA and sexually dimorphic neurodevelopmental disorders that are characterized by abnormalities in social behavior (autism, schizophrenia), we assessed sociability in male and female inbred mice (C57BL/6J) across postnatal development (N = 104) in relation to paternal age. We found differences in early social behavior in both male and female offspring of older breeders, with differences in this social domain persisting into adulthood in males only. We showed that these social deficits were not present in the fathers of these offspring, confirming a de novo origin of an altered social trajectory in the offspring generation. Our results, highly novel in rodent research, support the epidemiological observations in humans and provide evidence for a causal link between APA, age-related changes in the paternal sperm DNA and neurodevelopmental disorders in their offspring., (© 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Genetic and environmental factors play an important role in the cannabinoid modulation of motivation and emotion. Therefore, the aim of the present study was to test whether anandamide modulation of social behavior is strain- and context-dependent. We tested the effects of the anandamide hydrolysis inhibitor URB597 on social behavior and 50-kHz ultrasonic vocalizations (USVs) in adolescent and adult Wistar and Sprague-Dawley rats tested in different emotionally arousing conditions (familiarity/unfamiliarity to the test cage, low/high light). Under all experimental conditions, adolescent and adult Sprague-Dawley rats displayed higher levels of social behavior and emitted more 50-kHz USVs than Wistar rats. URB597 enhanced social play behavior in adolescent Wistar rats under all experimental conditions. However, URB597 only increased social interaction in adult Wistar rats under unfamiliar/high light conditions. URB597 did not affect adolescent social play behavior and adult social interaction in Sprague-Dawley rats under any experimental condition. Moreover, URB597 increased the USVs emitted during social interaction by adolescent Wistar and adult Sprague-Dawley rats tested under familiar/high light and unfamiliar/high light, respectively. These results show that anandamide has distinct roles in adolescent and adult social behaviors. Anandamide modulation of adolescent social play behavior is strain- but not context-dependent. Conversely, anandamide modulation of adult social behavior and USV emission depends upon both strain and experimental context. Furthermore, these results confirm that profound behavioral differences exist between Wistar and Sprague-Dawley rats, which may explain the sometimes contradictory effects of cannabinoid drugs on emotionality in different strains of rodents., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Positive social interactions during the juvenile and adolescent phases of life are essential for proper social and cognitive development in mammals, including humans. During this developmental period, there is a marked increase in peer-peer interactions, signified by the abundance of social play behaviour. Despite its importance for behavioural development, our knowledge of the neural underpinnings of social play behaviour is limited. Therefore, the purpose of this study was to map the neural circuits involved in social play behaviour in rats. This was achieved by examining cellular activity after social play using the immediate early gene c-Fos as a marker. After a session of social play behaviour, pronounced increases in c-Fos expression were observed in the medial prefrontal cortex, medial and ventral orbitofrontal cortex, dorsal striatum, nucleus accumbens core and shell, lateral amygdala, several thalamic nuclei, dorsal raphe and the pedunculopontine tegmental nucleus. Importantly, the cellular activity patterns after social play were topographically organized in this network, as indicated by play-specific correlations in c-Fos activity between regions with known direct connections. These correlations suggest involvement in social play behaviour of the projections from the medial prefrontal cortex to the striatum, and of amygdala and monoaminergic inputs to frontal cortex and striatum. The analyses presented here outline a topographically organized neural network implicated in processes such as reward, motivation and cognitive control over behaviour, which mediates social play behaviour in rats.

Rationale: Social play behavior is the most characteristic social behavior in young mammals. It is highly rewarding and crucial for proper neurobehavioral development. Despite the importance of genetic factors in normal and pathological social behaviors, little information is available about strain influences on social play., Objective and Methods: The aim of this study was to investigate differences in social play behavior, 50-kHz ultrasonic vocalizations (USVs) and their modulation by acute morphine and amphetamine administration in two rat strains widely used in behavioral pharmacology studies, i.e., Wistar and Sprague-Dawley rats., Results: Sprague-Dawley rats showed higher levels of social play than Wistar rats. In both strains, no correlation was found between the performance of social behaviors and the emission of 50-kHz USVs. In Wistar and Sprague-Dawley rats, morphine increased and amphetamine decreased social play. The effects of morphine, however, were more pronounced in Wistar than Sprague-Dawley animals. In both strains, morphine did not affect USV emission, while amphetamine increased it during cage exploration. In Sprague-Dawley rats only, amphetamine decreased USVs during social interaction., Conclusions: Wistar and Sprague-Dawley rats differ in their absolute levels of social play behavior and 50-kHz USVs, and quantitative differences exist in their response to pharmacological manipulations of social play. The emission of 50-kHz USVs and the behavioral parameters thought to reflect rewarding social interactions in adolescent rats are dissociable.

Rationale: Social play behavior is a characteristic form of social behavior displayed by juvenile and adolescent mammals. This social play behavior is highly rewarding and of major importance for social and cognitive development. Social play is known to be modulated by neurotransmitter systems involved in reward and motivation. Interestingly, psychostimulant drugs, such as amphetamine and cocaine, profoundly suppress social play, but the neural mechanisms underlying these effects remain to be elucidated., Objective: In this study, we investigated the pharmacological underpinnings of amphetamine- and cocaine-induced suppression of social play behavior in rats., Results: The play-suppressant effects of amphetamine were antagonized by the alpha-2 adrenoreceptor antagonist RX821002 but not by the dopamine receptor antagonist alpha-flupenthixol. Remarkably, the effects of cocaine on social play were not antagonized by alpha-2 noradrenergic, dopaminergic, or serotonergic receptor antagonists, administered either alone or in combination. The effects of a subeffective dose of cocaine were enhanced by a combination of subeffective doses of the serotonin reuptake inhibitor fluoxetine, the dopamine reuptake inhibitor GBR12909, and the noradrenaline reuptake inhibitor atomoxetine., Conclusions: Amphetamine, like methylphenidate, exerts its play-suppressant effect through alpha-2 noradrenergic receptors. On the other hand, cocaine reduces social play by simultaneous increases in dopamine, noradrenaline, and serotonin neurotransmission. In conclusion, psychostimulant drugs with different pharmacological profiles suppress social play behavior through distinct mechanisms. These data contribute to our understanding of the neural mechanisms of social behavior during an important developmental period, and of the deleterious effects of psychostimulant exposure thereon.

Social play behavior is the most vigorous and characteristic form of social interaction displayed by developing mammals. The laboratory rat is an ideal species to study this behavior, since it shows ample social play that can be easily recognized and quantified. In this chapter, we will first briefly describe the structure of social play behavior in rats. Next, we will discuss studies that used social isolation rearing during the period in life when social play is most abundant to investigate the developmental functions of social play behavior in rats, focusing on the consequences of play deprivation on social, cognitive, emotional, and sensorimotor development. Last, we will discuss the neural substrates of social play behavior in rats, with emphasis on the limbic corticostriatal circuits that underlie emotions and their influence on behavior.

The widespread use of tobacco and alcohol among adolescents might be related to the ability of nicotine and ethanol to facilitate social interactions. To investigate the neurobehavioral mechanisms underlying the prosocial effects of nicotine and ethanol, we focused on social play behavior, the most characteristic social activity in adolescent rats. Social play behavior is rewarding, and it is modulated through opioid, cannabinoid and dopaminergic neurotransmission, which are also involved in the reinforcing properties of nicotine and ethanol. We found that nicotine and ethanol increased social play, without affecting locomotion or social exploration. Their effects depended on the level of social activity of the partner, and were comparable in familiar and unfamiliar environments. At doses that increased social play, nicotine and ethanol had no anxiolytic effects in the elevated plus-maze. By contrast, the prototypical anxiolytic drug diazepam reduced social play at doses that reduced anxiety. The effects of nicotine on social play were blocked by the opioid receptor antagonist naloxone, the CB(1) cannabinoid receptor antagonist SR141716A, and the dopamine receptor antagonist alpha-flupenthixol. The effects of ethanol were blocked by SR141716A and alpha-flupenthixol, but not by naloxone. Combined administration of subeffective doses of nicotine and ethanol only modestly enhanced social play. These results show that the facilitatory effects of nicotine and ethanol on social play are behaviorally specific and mediated through neurotransmitter systems involved in positive emotions and motivation, through partially dissociable mechanisms. Furthermore, the stimulating effects of nicotine and ethanol on social play behavior are independent of their anxiolytic-like properties.

The endocannabinoid system plays an important role in the modulation of affect, motivation, and emotion. Social play behavior is a natural reinforcer in adolescent rats, and we have recently shown that interacting endocannabinoid, opioid, and dopamine systems modulate social play. In the present study, we tested the hypothesis that, in contrast to administration of exogenous cannabinoid agonists, increasing local endocannabinoid signaling through anandamide transporter inhibition enhances social play. To this aim, we tested the effects of two anandamide transporter inhibitors with different target selectivity on social play behavior in adolescent rats. Interestingly, we found that the prototypical anandamide transporter inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) reduced social play, whereas its more selective analog N-arachidonoyl-(2-methyl-4-hydroxyphenyl)amine (VDM11) enhanced it. The effects of AM404 were not mediated through its known pharmacological targets, since they were not blocked by the CB(1) cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A), the CB(2) cannabinoid receptor antagonist N-(1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide (SR144528), or by the transient receptor potential vanilloid 1 receptor antagonist capsazepine. In contrast, the increase in social play induced by VDM11 was dependent on cannabinoid, opioid, and dopaminergic neurotransmission, since it was blocked by the CB(1) cannabinoid receptor antagonist SR141716A, the opioid receptor antagonist naloxone, and the dopamine receptor antagonist alpha-flupenthixol. These findings support the notion that anandamide plays an important role in the modulation of social interaction in adolescent rats, and they suggest that selective anandamide transporter inhibitors might be useful for the treatment of social dysfunctions. Furthermore, these results suggest that off-target effects may be responsible for some of the conflicting effects of anandamide transporter inhibitors on behavior.

Methylphenidate is the first-choice treatment for attention-deficit/hyperactivity disorder (ADHD), but its mechanism of action is incompletely understood. The cognitive effects of methylphenidate have been extensively studied, but little is known about its effects on spontaneous social behavior. During adolescence, rats display a characteristic, highly vigorous form of social behavior, termed social play behavior, which is of critical importance for social and cognitive development. We investigated the neurobehavioral mechanisms by which methylphenidate affects social play behavior in rats. Methylphenidate (0.3-3.0 mg/kg, s.c. or p.o.) abolished social play behavior, without altering general social interest. This effect of methylphenidate did not depend upon the baseline level of social play and was not secondary to changes in locomotion. Furthermore, the play-suppressant effect of methylphenidate was not subject to tolerance or sensitization. Methylphenidate blocked both the initiation to play and the responsivity to play initiation. The effect of methylphenidate was mimicked by the noradrenaline reuptake inhibitor atomoxetine, which is also used for the treatment of ADHD, and was blocked by an alpha-2 adrenoceptor antagonist. In addition, combined administration of subeffective doses of methylphenidate and atomoxetine suppressed social play. However, blockade of alpha-1 adrenoceptors, beta-adrenoceptors, or dopamine receptors did not alter the effect of methylphenidate. These data show that methylphenidate selectively blocks the most vigorous part of the behavioral repertoire of adolescent rats through a noradrenergic mechanism. We suggest that the effect of methylphenidate on social play is a reflection of its therapeutic effect in ADHD, that is, improved behavioral inhibition. However, given the importance of social play for development, these findings may also indicate an adverse side effect of methylphenidate.

The isolation and identification, in 1964, of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, opened the door to a whole new field of medical research. The exploration of the therapeutic potential of THC and other natural and synthetic cannabinoid compounds was paralleled by the discovery of the endocannabinoid system, comprising cannabinoid receptors and their endogenous ligands, which offered exciting new insights into brain function. Besides its well-known involvement in specific brain functions, such as control of movement, memory and emotions, the endocannabinoid system plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation. For this reason, changes in its activity during stages of high neuronal plasticity, such as the perinatal and the adolescent period, can have long-lasting neurobehavioral consequences. Here, we summarize human and animal studies examining the behavioral and neurobiological effects of in utero and adolescent exposure to cannabis. Since cannabis preparations are widely used and abused by young people, including pregnant women, understanding how cannabinoid compounds affect the developing brain, leading to neurobehavioral alterations or neuropsychiatric disorders later in life, is a serious health issue. In addition, since the endocannabinoid system is emerging as a novel therapeutic target for the treatment of several neuropsychiatric diseases, a detailed investigation of possible adverse effects of cannabinoid compounds on the central nervous system (CNS) of immature individuals is warranted.