Opportunities for risk-taking during play alters cognitive performance and prefrontal inhibitory signalling in rats of both sexes.

Social play behaviour is a rewarding activity that can entail risks, thus allowing young individuals to test the limits of their capacities and to train their cognitive and emotional adaptability to challenges. Here, we tested in rats how opportunities for risk-taking during play affect the development of cognitive and emotional capacities and medial prefrontal cortex (mPFC) function, a brain structure important for risk-based decision making. Male and female rats were housed socially or social play-deprived (SPD) between postnatal day (P)21 and P42. During this period, half of both groups were daily exposed to a high-risk play environment. Around P85, all rats were tested for cognitive performance and emotional behaviour after which inhibitory currents were recorded in layer 5 pyramidal neurons in mPFC slices. We show that playing in a high-risk environment altered cognitive flexibility in both sexes and improved behavioural inhibition in males. High-risk play altered anxiety-like behaviour in the elevated plus maze in males and in the open field in females, respectively. SPD affected cognitive flexibility in both sexes and decreased anxiety-like behaviour in the elevated plus maze in females. We found that synaptic inhibitory currents in the mPFC were increased in male, but not female, rats after high-risk play, while SPD lowered prefrontal cortex (PFC) synaptic inhibition in both sexes. Together, our data show that exposure to risks during play affects the development of cognition, emotional behaviour and inhibition in the mPFC. Furthermore, our study suggests that the opportunity to take risks during play cannot substitute for social play behaviour.

Brain Microdialysate Monoamines in Relation to Circadian Rhythms, Sleep, and Sleep Deprivation - a Systematic Review, Network Meta-analysis, and New Primary Data.

Disruption of the monoaminergic system, e.g. by sleep deprivation (SD), seems to promote certain diseases. Assessment of monoamine levels over the circadian cycle, during different sleep stages and during SD is instrumental to understand the molecular dynamics during and after SD. To provide a complete overview of all available evidence, we performed a systematic review. A comprehensive search was performed for microdialysis and certain monoamines (dopamine, serotonin, noradrenaline, adrenaline), certain monoamine metabolites (3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA)) and a precursor (5-hydroxytryptophan (5-HTP)) in PubMed and EMBASE. After screening of the search results by two independent reviewers, 94 publications were included. All results were tabulated and described qualitatively. Network-meta analyses (NMAs) were performed to compare noradrenaline and serotonin concentrations between sleep stages. We further present experimental monoamine data from the medial prefrontal cortical (mPFC). Monoamine levels varied with brain region and circadian cycle. During sleep, monoamine levels generally decreased compared to wake. These qualitative observations were supported by the NMAs: noradrenaline and serotonin levels decreased from wakefulness to slow wave sleep and decreased further during Rapid Eye Movement sleep. In contrast, monoamine levels generally increased during SD, and sometimes remained high even during subsequent recovery. Decreases during or after SD were only reported for serotonin. In our experiment, SD did not affect any of the mPFC monoamine levels. Concluding, monoamine levels vary over the light-dark cycle and between sleep stages. SD modifies the patterns, with effects sometimes lasting beyond the SD period.

Combined fetal inflammation and postnatal hypoxia causes myelin deficits and autism-like behavior in a rat model of diffuse white matter injury.

Diffuse white matter injury (WMI) is a serious problem in extremely preterm infants, and is associated with adverse neurodevelopmental outcome, including cognitive impairments and an increased risk of autism-spectrum disorders. Important risk factors include fetal or perinatal inflammatory insults and fluctuating cerebral oxygenation. However, the exact mechanisms underlying diffuse WMI are not fully understood and no treatment options are currently available. The use of clinically relevant animal models is crucial to advance knowledge on the pathophysiology of diffuse WMI, allowing the definition of novel therapeutic targets. In the present study, we developed a multiple-hit animal model of diffuse WMI by combining fetal inflammation and postnatal hypoxia in rats. We characterized the effects on white matter development and functional outcome by immunohistochemistry, MRI and behavioral paradigms. Combined fetal inflammation and postnatal hypoxia resulted in delayed cortical myelination, microglia activation and astrogliosis at P18, together with long-term changes in oligodendrocyte maturation as observed in 10 week old animals. Furthermore, rats with WMI showed impaired motor performance, increased anxiety and signs of autism-like behavior, i.e. reduced social play behavior and increased repetitive grooming. In conclusion, the combination of fetal inflammation and postnatal hypoxia in rats induces a pattern of brain injury and functional impairments that closely resembles the clinical situation of diffuse WMI. This animal model provides the opportunity to elucidate pathophysiological mechanisms underlying WMI, and can be used to develop novel treatment options for diffuse WMI in preterm infants.

Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats.

Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD.

Dissociating the role of endocannabinoids in the pleasurable and motivational properties of social play behaviour in rats.

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.

Glucocorticoid receptor antagonism disrupts the reconsolidation of social reward-related memories in rats.

Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use. Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated, reconsolidation of memories of physiologically relevant social rewards has received little attention. Social play, the most characteristic social behaviour displayed by young mammals, is highly rewarding, illustrated by the fact that it can induce conditioned place preference (CPP). Here, we investigated the role of signalling mechanisms implicated in memory processes, including reconsolidation, namely glucocorticoid, mineralocorticoid, NMDA glutamatergic and CB1 cannabinoid receptors, in the reconsolidation of social play-induced CPP in rats. Systemic treatment with the glucocorticoid receptor antagonist mifepristone before, but not immediately after, retrieval disrupted the reconsolidation of social play-induced CPP. Mifepristone did not affect social play-induced CPP in the absence of memory retrieval. Treatment with the NMDA receptor antagonist MK-801 modestly affected the reconsolidation of social play-induced CPP. However, the reconsolidation of social play-induced CPP was not affected by treatment with the mineralocorticoid and CB1 cannabinoid receptor antagonists spironolactone and rimonabant, respectively. We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward-related memories in rats. These data indicate that the neural mechanisms of the reconsolidation of social reward-related memories only partially overlap with those underlying the reconsolidation of other reward-related memories.

Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia.

RATIONALE: Genetic and environmental factors cause neuropsychiatric disorders through complex interactions that are far from understood. Loss-of-function mutations in synaptic proteins like neurexin1α have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), both characterised by problems in social behaviour. Childhood social play behaviour is thought to facilitate social development, and lack of social play may precipitate or exacerbate ASD and SCZ. OBJECTIVE: To test the hypothesis that an environmental insult acts on top of genetic vulnerability to precipitate psychiatric-like phenotypes. To that aim, social behaviour in neurexin1α knockout rats was assessed, with or without deprivation of juvenile social play. We also tested drugs prescribed in ASD or SCZ to assess the relevance of this dual-hit model for these disorders. RESULTS: Neurexin1α knockout rats showed an aberrant social phenotype, with high amounts of social play, increased motivation to play, age-inappropriate sexual mounting, and an increase in general activity. Play deprivation subtly altered later social behaviour, but did not affect the phenotype of neurexin1α knockout rats. Risperidone and methylphenidate decreased play behaviour in both wild-type and knockout rats. Amphetamine-induced hyperactivity was exaggerated in neurexin1α knockout rats. CONCLUSION: Deletion of the neurexin1α gene in rats causes exaggerated social play, which is not modified by social play deprivation. This phenotype therefore resembles disinhibited behaviour rather than the social withdrawal seen in ASD and SCZ. The neurexin1α knockout rat could be a model for inappropriate or disinhibited social behaviour seen in childhood mental disorders.

Ultrasonic vocalization emission is altered following neonatal hypoxic-ischemic brain injury in mice.

Neonatal hypoxic-ischemic (HI) brain injury leads to cognitive impairments including social communication disabilities. Current treatments do not sufficiently target these impairments, therefore new tools are needed to examine social communication in models for neonatal brain injury. Ultrasonic vocalizations (USVs) during early life show potential as a measurement for social development and reflect landmark developmental stages in neonatal mice. However, changes in USV emission early after HI injury have not been found yet. Our current study examines USV patterns and classes in the first 3 days after HI injury. C57Bl/6 mice were subjected to HI on postnatal day (P)9 and USVs were recorded between P10 and P12. Audio files were analyzed using the VocalMat automated tool. HI-injured mice emitted less USVs, for shorter durations, and at a higher frequency compared to control (sham-operated) littermates. The HI-induced alterations in USVs were most distinct at P10 and in the frequency range of 50-75 kHz. At P10 HI-injured mouse pups also produced different ratios of USV class types compared to control littermates. Moreover, alterations in the duration and frequency were specific to certain USV classes in HI animals compared to controls. Injury in the striatum and hippocampus contributed most to alterations in USV communication after HI. Overall, neonatal HI injury leads to USV alterations in newborn mice which could be used as a tool to study early HI-related social communication deficits.

The neurobiology of social play behaviour: Past, present and future.

Social play behaviour is a highly energetic and rewarding activity that is of great importance for the development of brain and behaviour. Social play is abundant during the juvenile and early adolescent phases of life, and it occurs in most mammalian species, as well as in certain birds and reptiles. To date, the majority of research into the neural mechanisms of social play behaviour has been performed in male rats. In the present review we summarize studies on the neurobiology of social play behaviour in rats, including work on pharmacological and genetic models for autism spectrum disorders, early life manipulations and environmental factors that influence play in rats. We describe several recent developments that expand the field, and highlight outstanding questions that may guide future studies.

Nucleus accumbens µ-opioid receptors mediate social reward.

Positive social interactions are essential for emotional well-being and proper behavioral development of young individuals. Here, we studied the neural underpinnings of social reward by investigating the involvement of opioid neurotransmission in the nucleus accumbens (NAc) in social play behavior, a highly rewarding social interaction in adolescent rats. Intra-NAc infusion of morphine (0.05-0.1 µg) increased pinning and pouncing, characteristic elements of social play behavior in rats, and blockade of NAc opioid receptors with naloxone (0.5 µg) prevented the play-enhancing effects of systemic morphine (1 mg/kg, s.c.) administration. Thus, stimulation of opioid receptors in the NAc was necessary and sufficient for morphine to increase social play. Intra-NAc treatment with the selective µ-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly(5)-ol]enkephalin (DAMGO) (0.1-10 ng) and the µ-opioid receptor antagonist Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) (0.3-3 µg) increased and decreased social play, respectively. The δ-opioid receptor agonist DPDPE ([D-Pen(2),D-Pen(5)]-enkephalin) (0.3-3 µg) had no effects, whereas the κ-opioid receptor agonist U69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-(pyrrolidin-1-yl)-1-oxaspiro[4.5]dec-8-yl]acetamide) (0.01-1 µg) decreased social play. Intra-NAc treatment with ß-endorphin (0.01-1 µg) increased social play, but met-enkephalin (0.1-5 µg) and the enkephalinase inhibitor thiorphan (0.1-1 µg) were ineffective. DAMGO (0.1-10 ng) increased social play after infusion into both the shell and core subregions of the NAc. Last, intra-NAc infusion of CTAP (3 µg) prevented the development of social play-induced conditioned place preference. These findings identify NAc µ-opioid receptor stimulation as an important neural mechanism for the attribution of positive value to social interactions in adolescent rats. Altered NAc µ-opioid receptor function may underlie social impairments in psychiatric disorders such as autism, schizophrenia, or personality disorders.

Cognitive performance during adulthood in a rat model of neonatal diffuse white matter injury.

RATIONALE: Infants born prematurely risk developing diffuse white matter injury (WMI), which is associated with impaired cognitive functioning and an increased risk of autism spectrum disorder. Recently, our rat model of preterm diffuse WMI induced by combined fetal inflammation and postnatal hypoxia showed impaired motor performance, anxiety-like behaviour and autism-like behaviour in juvenile rats, especially males. Immunohistochemistry showed delayed myelination in the sensory cortex and impaired oligodendrocyte differentiation. OBJECTIVE: To assess long-term cognitive deficits in this double-hit rat model of diffuse WMI, animals were screened on impulsivity, attention and cognitive flexibility in adulthood using the 5-choice serial reaction time task (5CSRTT) and a probabilistic reversal learning task, tests that require a proper functioning prefrontal cortex. Thereafter, myelination deficits were evaluated by immunofluorescent staining in adulthood. RESULTS: Overall, little effect of WMI or sex was found in the cognitive tasks. WMI animals showed subtle differences in performance in the 5CSRTT. Manipulating 5CSRTT parameters resulted in performance patterns previously seen in the literature. Sex differences were found in perseverative responses and omitted trials: female WMI rats seem to be less flexible in the 5CSRTT but not in the reversal learning task. Males collected rewards faster in the probabilistic reversal learning task. These findings are explained by temporally rather than permanently affected myelination and by the absence of extensive injury to prefrontal cortical subregions, confirmed by immunofluorescent staining in both adolescence and adulthood. CONCLUSION: This rat model of preterm WMI does not lead to long-term cognitive deficits as observed in prematurely born human infants.

Individual differences in social play behaviour predict alcohol intake and control over alcohol seeking in rats.

RATIONALE: Social play behaviour is a rewarding social activity displayed by young mammals, thought to be important for the development of brain and behaviour. Indeed, disruptions of social play behaviour in rodents have been associated with cognitive deficits and augmented sensitivity to self-administration of substances of abuse, including alcohol, later in life. However, the relation between social development and loss of control over substance use, a key characteristic of substance use disorders including alcohol use disorder (AUD), has not been investigated. Moreover, it remains unknown how inherent differences in playfulness relate to differences in the sensitivity to substance use and AUD. OBJECTIVE: The objective of this study is to determine how individual differences in juvenile social play behaviour predict alcohol intake and loss of control over alcohol seeking. METHODS: Juvenile male Lister hooded rats were characterized for their tendency to engage in social play behaviour. Subsequently, alcohol consumption and conditioned suppression of alcohol seeking were assessed in the tertiles of rats that showed the most and least social play. RESULTS: The rats that engaged most in social play behaviour consumed more alcohol than their less playful counterparts. However, whereas the most playful rats showed intact conditioned suppression of alcohol seeking, the least playful rats showed no such suppression. CONCLUSION: Individual levels of playfulness predict the sensitivity to alcohol-directed behaviour. Highly playful rats are more prone to alcohol intake, yet show greater control over alcohol seeking. These findings increase our understanding of the relationship between social development and vulnerability to AUD.

On the central noradrenergic mechanism underlying the social play-suppressant effect of methylphenidate in rats.

Social play behaviour is a vigorous, highly rewarding social activity abundant in the young of most mammalian species, including humans. Social play is thought to be important for social, emotional and cognitive development, yet its neural underpinnings are incompletely understood. We have previously shown that low doses of methylphenidate suppress social play behaviour through a noradrenergic mechanism of action, and that methylphenidate exerts its effect within the prefrontal cortex, amygdala and habenula. In the present study, we sought to reveal whether these regions work in parallel or in series to mediate the play-suppressant effect of methylphenidate. To that aim, we tested whether infusion of the α2-adrenoceptor antagonist RX821002 into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala or habenula prevents the effect of methylphenidate on social play behaviour, or the psychomotor stimulant effect of methylphenidate. We found that the social play-suppressant effect of methylphenidate was not prevented by infusion of the α2-adrenoceptor antagonist into either region, or by infusion of RX821002 into both the anterior cingulate and infralimbic cortex. By contrast, RX821002 infusion into the anterior cingulate modestly enhanced social play, and infusion of the antagonist into the infralimbic cortex attenuated the psychomotor stimulant effect of methylphenidate. We conclude that there is redundancy in the neural circuitry that mediates the play-suppressant effect of methylphenidate, whereby prefrontal cortical and subcortical limbic mechanisms act in parallel. Moreover, our data support the notion that prefrontal noradrenergic mechanisms contribute to the locomotor enhancing effect of psychostimulant drugs.

Healthy play, better coping: The importance of play for the development of children in health and disease.

Play is of vital importance for the healthy development of children. From a developmental perspective, play offers ample physical, emotional, cognitive, and social benefits. It allows children and adolescents to develop motor skills, experiment with their (social) behavioural repertoire, simulate alternative scenarios, and address the various positive and negative consequences of their behaviour in a safe and engaging context. Children with a chronic or life-threatening disease may face obstacles that negatively impact play and play development, possibly impeding developmental milestones, beyond the actual illness itself. Currently, there is limited understanding of the impact of (1) aberrant or suppressed play and (2) play-related interventions on the development of chronic diseased children. We argue that stimulating play behaviour enhances the adaptability of a child to a (chronic) stressful condition and promotes cognitive, social, emotional and psychomotor functioning, thereby strengthening the basis for their future health. Systematic play research will help to develop interventions for young patients, to better cope with the negative consequences of their illness and stimulate healthy development.

The neurobiology of social play and its rewarding value in rats.

In the young of many mammalian species, including humans, a vigorous and highly rewarding social activity is abundantly expressed, known as social play behaviour. Social play is thought to be important for the development of social, cognitive and emotional processes and their neural underpinnings, and it is disrupted in pediatric psychiatric disorders. Here, we summarize recent progress in our understanding of the brain mechanisms of social play behaviour, with a focus on its rewarding properties. Opioid, endocannabinoid, dopamine and noradrenaline systems play a prominent role in the modulation of social play. Of these, dopamine is particularly important for the motivational properties of social play. The nucleus accumbens has been identified as a key site for opioid and dopamine modulation of social play. Endocannabinoid influences on social play rely on the basolateral amygdala, whereas noradrenaline modulates social play through the basolateral amygdala, habenula and prefrontal cortex. In sum, social play behaviour is the result of coordinated activity in a network of corticolimbic structures, and its monoamine, opioid and endocannabinoid innervation.

Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats.

Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.

Amphetamine and cocaine suppress social play behavior in rats through distinct mechanisms.

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.

ß-Adrenoreceptor stimulation mediates reconsolidation of social reward-related memories.

BACKGROUND: In recent years, the notion that consolidated memories become transiently unstable after retrieval and require reconsolidation to persist for later use has received strong experimental support. To date, the majority of studies on reconsolidation have focused on memories of negative emotions, while the dynamics of positive memories have been less well studied. Social play, the most characteristic social behavior displayed by young mammals, is important for social and cognitive development. It has strong rewarding properties, illustrated by the fact that it can induce conditioned place preference (CPP). In order to understand the dynamics of positive social memories, we evaluated the effect of propranolol, a ß-adrenoreceptor antagonist known to influence a variety of memory processes, on acquisition, consolidation, retrieval and reconsolidation of social play-induced CPP in adolescent rats. METHODOLOGY/PRINCIPAL FINDINGS: Systemic treatment with propranolol, immediately before or after a CPP test (i.e. retrieval session), attenuated CPP 24 h later. Following extinction, CPP could be reinstated in saline--but not in propranolol-treated rats, indicating that propranolol treatment had persistently disrupted the CPP memory trace. Propranolol did not affect social play-induced CPP in the absence of memory retrieval or when administered 1 h or 6 h after retrieval. Furthermore, propranolol did not affect acquisition, consolidation or retrieval of social play-induced CPP. CONCLUSIONS/SIGNIFICANCE: We conclude that ß-adrenergic neurotransmission selectively mediates the reconsolidation, but not other processes involved in the storage and stability of social reward-related memories in adolescent rats. These data support the notion that consolidation and reconsolidation of social reward-related memories in adolescent rats rely on distinct neural mechanisms.