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.

Social play behavior shapes the development of prefrontal inhibition in a region-specific manner.

Experience-dependent organization of neuronal connectivity is critical for brain development. We recently demonstrated the importance of social play behavior for the developmental fine-tuning of inhibitory synapses in the medial prefrontal cortex in rats. When these effects of play experience occur and if this happens uniformly throughout the prefrontal cortex is currently unclear. Here we report important temporal and regional heterogeneity in the impact of social play on the development of excitatory and inhibitory neurotransmission in the medial prefrontal cortex and the orbitofrontal cortex. We recorded in layer 5 pyramidal neurons from juvenile (postnatal day (P)21), adolescent (P42), and adult (P85) rats after social play deprivation (between P21 and P42). The development of these prefrontal cortex subregions followed different trajectories. On P21, inhibitory and excitatory synaptic input was higher in the orbitofrontal cortex than in the medial prefrontal cortex. Social play deprivation did not affect excitatory currents, but reduced inhibitory transmission in both medial prefrontal cortex and orbitofrontal cortex. Intriguingly, the reduction occurred in the medial prefrontal cortex during social play deprivation, whereas the reduction in the orbitofrontal cortex only became manifested after social play deprivation. These data reveal a complex interaction between social play experience and the specific developmental trajectories of prefrontal subregions.

Social Play Behavior Is Critical for the Development of Prefrontal Inhibitory Synapses and Cognitive Flexibility in Rats.

Sensory driven activity during early life is critical for setting up the proper connectivity of the sensory cortices. We ask here whether social play behavior, a particular form of social interaction that is highly abundant during postweaning development, is equally important for setting up connections in the developing prefrontal cortex (PFC). Young male rats were deprived from social play with peers during the period in life when social play behavior normally peaks [postnatal day 21-42] (SPD rats), followed by resocialization until adulthood. We recorded synaptic currents in layer 5 cells in slices from medial PFC of adult SPD and control rats and observed that inhibitory synaptic currents were reduced in SPD slices, while excitatory synaptic currents were unaffected. This was associated with a decrease in perisomatic inhibitory synapses from parvalbumin-positive GABAergic cells. In parallel experiments, adult SPD rats achieved more reversals in a probabilistic reversal learning (PRL) task, which depends on the integrity of the PFC, by using a more simplified cognitive strategy than controls. Interestingly, we observed that one daily hour of play during SPD partially rescued the behavioral performance in the PRL, but did not prevent the decrease in PFC inhibitory synaptic inputs. Our data demonstrate the importance of unrestricted social play for the development of inhibitory synapses in the PFC and cognitive skills in adulthood and show that specific synaptic alterations in the PFC can result in a complex behavioral outcome.SIGNIFICANCE STATEMENT This study addressed the question whether social play behavior in juvenile rats contributes to functional development of the prefrontal cortex (PFC). We found that rats that had been deprived from juvenile social play (social play deprivation - SPD) showed a reduction in inhibitory synapses in the PFC and a simplified strategy to solve a complex behavioral task in adulthood. Providing one daily hour of play during SPD partially rescued the cognitive skills in these rats, but did not prevent the reduction in PFC inhibitory synapses. Our results demonstrate a key role for unrestricted juvenile social play in PFC development and emphasize the complex relation between PFC circuit connectivity and cognitive function.

Temporally Specific Roles of Ventral Tegmental Area Projections to the Nucleus Accumbens and Prefrontal Cortex in Attention and Impulse Control.

Deficits in impulse control and attention are prominent in the symptomatology of mental disorders such as attention deficit hyperactivity disorder (ADHD), substance addiction, schizophrenia, and bipolar disorder, yet the underlying mechanisms are incompletely understood. Frontostriatal structures, such as the nucleus accumbens (NAcb), the medial prefrontal cortex (mPFC), and their dopaminergic innervation from the ventral tegmental area (VTA) have been implicated in impulse control and attention. What remains unclear is how the temporal pattern of activity of these VTA projections contributes to these processes. Here, we optogenetically stimulated VTA dopamine (DA) cells, as well as VTA projections to the NAcb core (NAcbC), NAcb shell (NAcbS), and the mPFC in male rats performing the 5-choice serial reaction time task (5-CSRTT). Our data show that stimulation of VTA DA neurons, and VTA projections to the NAcbC and the mPFC immediately before presentation of the stimulus cue, impaired attention but spared impulse control. Importantly, in addition to reducing attention, activation of VTA-NAcbS also increased impulsivity when tested under a longer intertrial interval (ITI), to provoke impulsive behavior. Optogenetic stimulation at the beginning of the ITI only partially replicated these effects. In sum, our data show how attention and impulsivity are modulated by neuronal activity in distinct ascending output pathways from the VTA in a temporally specific manner. These findings increase our understanding of the intricate mechanisms by which mesocorticolimbic circuits contribute to cognition.SIGNIFICANCE STATEMENT Deficits in impulse control and attention are prominent in the symptomatology of several mental disorders, yet the brain mechanisms involved are incompletely understood. Since frontostriatal circuits have been implicated in impulse control and attention, we here examined the role of ascending projections from the midbrain ventral tegmental area (VTA) to the nucleus accumbens (NAcb) and prefrontal cortex (PFC). Using optogenetics to individually stimulate these projections with time-locked precision, we distinguished the role that each of these projections plays, in both impulse control and attention. As such, our study enhances our understanding of the neuronal circuitry that drives impulsive and attentive behavior.

Baclofen and naltrexone, but not N-acetylcysteine, affect voluntary alcohol drinking in rats regardless of individual levels of alcohol intake.

In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.

Corticolimbic Mechanisms of Behavioral Inhibition under Threat of Punishment.

Being able to limit the pursuit of reward to prevent negative consequences is an important expression of behavioral inhibition. Everyday examples of an inability to exert such control over behavior are the overconsumption of food and drugs of abuse, which are important factors in the development of obesity and addiction, respectively. Here, we use a behavioral task that assesses the ability of male rats to exert behavioral restraint at the mere sight of palatable food during the presentation of an audiovisual threat cue to investigate the corticolimbic underpinnings of behavioral inhibition. We demonstrate a prominent role for the medial prefrontal cortex in the exertion of control over behavior under threat of punishment. Moreover, task engagement relies on function of the ventral striatum, whereas the basolateral amygdala mediates processing of the threat cue. Together, these data show that inhibition of reward pursuit requires the coordinated action of a network of corticolimbic structures.SIGNIFICANCE STATEMENT There is a need for translational models that allow to dissect mechanisms underlying the processes involved in controlling behavior. In this study, we present a novel behavioral task that assesses the ability of rats to exert behavioral restraint over the consumption of a visually present sucrose pellet during the presentation of an audiovisual threat cue. This task requires relatively little behavioral training and it discerns distinct behavioral impairments, including a failure to retrieve stimulus value, a reduced task engagement, and compromised inhibition of behavior. Using pharmacological inactivations of different regions of the corticolimbic system of the rat, we demonstrate dissociable roles for the prefrontal cortex, amygdala, and striatum in inhibition of reward pursuit under threat of punishment.

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.

Heterogeneous neuronal activity in the lateral habenula after short- and long-term cocaine self-administration in rats.

Cocaine addiction is thought to be the result of drug-induced functional changes in a neural network implicated in emotions, learning and cognitive control. Recent studies have implicated the lateral habenula (LHb) in drug-directed behavior, especially its aversive aspects. Limited cocaine exposure has been shown to alter neuronal activity in the LHb, but the impact of long-term drug exposure on habenula function has not been determined. Therefore, using c-fos as a marker, we here examined neuronal activity in LHb in rats that self-administered cocaine for either 10 or 60 days. Both the density of labeled cells and the cellular labeling intensity were measured in the lateral (LHbL) and medial (LHbM) parts of LHb. After 10 days of cocaine self-administration, both the density and intensity of c-fos-positive cells were significantly increased in LHbL, but not LHbM, while after 60 days, an increased density (but not intensity) of labeled neurons in both LHbL and LHbM was observed. Most c-fos-labeled neurons were glutamatergic. In addition, we found increased GAD65 expression after 10 but not 60 days of cocaine self-administration in the rostral mesencephalic tegmental nucleus. These data shed light on the complex temporal dynamics by which cocaine self-administration alters activity in LHb circuitry, which may play an important role in the descent to compulsive drug use as a result of prolonged cocaine-taking experience.

Dopaminergic neurotransmission in ventral and dorsal striatum differentially modulates alcohol reinforcement.

Dopaminergic neurotransmission in the striatum has been widely implicated in the reinforcing properties of substances of abuse. However, the striatum is functionally heterogeneous, and previous work has mostly focused on psychostimulant drugs. Therefore, we investigated how dopamine within striatal subregions modulates alcohol-directed behaviour in rats. We assessed the effects of infusion of the dopamine receptor antagonist alpha-flupenthixol into the shell and core of the nucleus accumbens (NAcc) and the dorsolateral striatum (DLS) on responding for alcohol under fixed ratio 1 (FR1) and progressive ratio (PR) schedules of reinforcement. Bilateral infusion of alpha-flupenthixol into the NAcc shell reduced responding for alcohol under both the FR1 (15 µg/side) and the PR schedule (3.75-15 µg/side) of reinforcement. Infusion of alpha-flupenthixol into the NAcc core (7.5-15 µg/side) also decreased responding for alcohol under both schedules. By contrast, alpha-flupenthixol infusion into the DLS did not affect FR1 responding, but reduced responding under the PR schedule (15 µg/side). The decreases in responding were related to earlier termination of responding during the session, whereas the onset and rate of responding remained largely unaffected. Together, these data suggest that dopamine in the NAcc shell is involved in the incentive motivation for alcohol, whereas DLS dopamine comes into play when obtaining alcohol requires high levels of effort. In contrast, NAcc core dopamine appears to play a more general role in alcohol reinforcement. In conclusion, dopaminergic neurotransmission acts in concert in subregions of the striatum to modulate different aspects of alcohol-directed behaviour.

Genetic Variability in Adenosine Deaminase-Like Contributes to Variation in Alcohol Preference in Mice.

BACKGROUND: A substantial part of the risk for alcohol use disorder is determined by genetic factors. We previously used chromosome substitution (CSS) mice, to identify a quantitative trait loci (QTL) for alcohol preference on mouse chromosome 2. The aim of this study was to identify candidate genes within this QTL that confer the risk for alcohol preference. METHODS: In order to delineate the neurobiological underpinnings of alcohol consumption, we expanded on the QTL approach to identify candidate genes for high alcohol preference in mice. We narrowed down a QTL for alcohol preference on mouse chromosome 2, that we previously identified using CSS mice, to 4 candidate genes in silico. Expression levels of these candidate genes in prefrontal cortex, amygdala, and nucleus accumbens-brain regions implicated in reward and addiction-were subsequently compared for the CSS-2 and the C57BL/6J host strain. RESULTS: We observed increased expression of adenosine deaminase-like (Adal) in all 3 regions in CSS-2 mice. Moreover, we found that the adenosine deaminase inhibitor EHNA reduced the difference in alcohol preference between CSS-2 and C57BL/6J mice. CONCLUSIONS: This study identifies Adal as a genetically protective factor against alcohol consumption in mice, in which elevated Adal levels contribute to low alcohol preference.

Loss of control over alcohol seeking in rats depends on individual vulnerability and duration of alcohol consumption experience.

Alcohol use disorder (AUD) is characterized by excessive alcohol use and persistent alcohol seeking despite knowledge of its negative consequences. Importantly, AUD typically develops after chronic excessive alcohol use in a subgroup of individuals who drink alcohol, suggesting that AUD results from an interaction between individual vulnerability and prolonged alcohol exposure. The present study assessed the contribution of prolonged exposure to alcohol and individual levels of alcohol intake to the development of loss of control over alcohol seeking in a conditioned suppression model. To investigate the impact of prolonged alcohol exposure, conditioned suppression of alcohol seeking was assessed after 2 and 4 months of intermittent alcohol access (IAA) in a subgroup of rats drinking moderate amounts of alcohol. We observed that suppression of alcohol seeking was reduced after 4 months compared with 2 months of IAA. The influence of individual levels of alcohol intake on loss of control over alcohol seeking was subsequently determined by assessing conditioned suppression in subgroups of low and high alcohol drinking rats. Unlike the low alcohol drinking rats, the high alcohol drinking rats showed aversion-resistant alcohol seeking after 2 months of IAA, although both groups showed comparable levels of conditioned freezing. These findings show that the development of loss of control over alcohol seeking, a key characteristic of AUD in humans, is dependent on both the extent of alcohol exposure and the individual's propensity to consume alcohol.

Stable immediate early gene expression patterns in medial prefrontal cortex and striatum after long-term cocaine self-administration.

The transition from casual to compulsive drug use is thought to occur as a consequence of repeated drug taking leading to neuroadaptive changes in brain circuitry involved in emotion and cognition. At the basis of such neuroadaptations lie changes in the expression of immediate early genes (IEGs) implicated in transcriptional regulation, synaptic plasticity and intracellular signalling. However, little is known about how IEG expression patterns change during long-term drug self-administration. The present study, therefore, compares the effects of 10 and 60-day self-administration of cocaine and sucrose on the expression of 17 IEGs in brain regions implicated in addictive behaviour, i.e. dorsal striatum, ventral striatum and medial prefrontal cortex (mPFC). Increased expression after cocaine self-administration was found for 6 IEGs in dorsal and ventral striatum (c-fos, Mkp1, Fosb/ΔFosb, Egr2, Egr4, and Arc) and 10 IEGs in mPFC (same 6 IEGs as in striatum, plus Bdnf, Homer1, Sgk1 and Rgs2). Five of these 10 IEGs (Egr2, Fosb/ΔFosb, Bdnf, Homer1 and Jun) and Trkb in mPFC were responsive to long-term sucrose self-administration. Importantly, no major differences were found between IEG expression patterns after 10 or 60 days of cocaine self-administration, except Fosb/ΔFosb in dorsal striatum and Egr2 in mPFC, whereas the amount of cocaine obtained per session was comparable for short-term and long-term self-administration. These steady changes in IEG expression are, therefore, associated with stable self-administration behaviour rather than the total amount of cocaine consumed. Thus, sustained impulses to IEG regulation during prolonged cocaine self-administration may evoke neuroplastic changes underlying compulsive drug use.

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.

Individual Variation in Alcohol Intake Predicts Reinforcement, Motivation, and Compulsive Alcohol Use in Rats.

BACKGROUND: Alcohol is one of the most commonly used psychoactive substances. Prolonged alcohol use can result in alcohol use disorder (AUD), characterized by excessive and compulsive alcohol consumption. Importantly, however, the development of AUD only happens in a minority of individuals who consume alcohol. To understand the individual vulnerability for AUD, models that capture both the individual variability in alcohol consumption and the transition from casual to compulsive alcohol use are essential. METHODS: Individual variability in voluntary alcohol intake and the preference for alcohol were assessed under continuous alcohol access (CAA) and intermittent-every-other-day alcohol access (IAA) schedules in the home cage using outbred Lister Hooded rats. Subsequently, the reinforcing properties of alcohol were tested in an operant setting. In subsequent experiments, we performed a quinine adulteration experiment to assess inflexible alcohol consumption and blood alcohol levels (BALs) were assessed after voluntary alcohol consumption. RESULTS: We found marked individual differences in alcohol consumption and preference under both access schedules, whereby subgroups of high- and low-alcohol-drinking rats (HD and LD) could be identified. HD with IAA increased their alcohol intake over days in the first month, whereas LD did not. Moreover, when alcohol access time was extended from 7 to 24 h/d for rats with IAA, alcohol intake profoundly increased in HD with IAA, whereas LD with IAA maintained low levels of alcohol intake. Furthermore, HD earned more alcohol than LD under both fixed ratio and progressive ratio schedules of reinforcement. We further found that HD continued their intake of a quinine-adulterated alcohol solution to a larger extent than LD and HD showed higher BALs after 30 minutes of alcohol consumption. CONCLUSIONS: These profound individual differences in alcohol intake, reinforcement, motivation, and AUD-like behavior provide a promising tool to unravel the neurobehavioral underpinnings of individual vulnerability for AUD.

Modeling autism-relevant behavioral phenotypes in rats and mice: Do 'autistic' rodents exist?

Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets.

The nucleus accumbens shell and the dorsolateral striatum mediate the reinforcing effects of cocaine through a serial connection.

The reinforcing and addictive properties of cocaine are thought to rely on the dopaminergic innervation of the striatum. The ventromedial [i.e. nucleus accumbens shell (NAcc) shell] and dorsolateral [dorsolateral striatum (DLS)] regions of the striatum are serially connected, and it is thought that slowly developing neuroadaptations are responsible for the recruitment of the DLS in mediating habitual drug use after extended drug experience. Remarkably, we have recently shown that the DLS is also involved in cocaine self-administration after limited use, to modulate the reinforcing properties of the drug, a function usually ascribed to the NAcc shell. Here, we investigated whether the involvement of the DLS in cocaine reinforcement requires dopaminergic activity within the NAcc shell, by performing a pharmacological disconnection study. We infused the dopamine receptor antagonist α-flupenthixol unilaterally into the NAcc shell and infused this same antagonist into the contralateral DLS, thereby disrupting dopaminergic interconnectivity within the striatum. We show that this disconnection results in increased responding for cocaine under a fixed ratio-1 schedule of reinforcement in rats with limited cocaine experience. These data suggest that a functional dopaminergic interaction between the NAcc shell and the DLS mediates cocaine reinforcement during the early stages of drug use.

Early social isolation augments alcohol consumption in rats.

There is a considerable degree of individual vulnerability for alcohol use disorder (AUD) as only a subpopulation of individuals who regularly consume alcohol develop AUD. It is therefore very important to understand the factors and mechanisms that contribute towards the individual risk for AUD. In this respect, social influences, in particular during development, may be relevant for AUD as disruptions in early social experiences are associated with an increased risk for AUD. Social play, the most prominent form of social behaviour shown by young mammals, is rewarding and considered to be important for social, emotional and cognitive development. Recent studies suggest that early social isolation, effectively depriving animals from social play, increases the risk for addictive behaviour. The aim of this study was therefore to explore the long-term consequences of early social isolation on alcohol consumption and motivation for alcohol. To this end, rats were socially isolated from postnatal days 21-42, followed by 4 weeks of social housing, and voluntary alcohol consumption and operant responding for alcohol were determined in adulthood. We observed enhanced levels of alcohol consumption in adulthood in previously isolated rats, whereas operant responding for alcohol was not altered. The impact of early social isolation was independent of the individual variation in alcohol consumption. These data indicate that social isolation, during a developmental period when social play is highly abundant, enhances the propensity to consume alcohol in adulthood. This implies that early social experience may be a protective factor against excessive alcohol use.

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.

New developments in human neurocognition: clinical, genetic, and brain imaging correlates of impulsivity and compulsivity.

Impulsivity and compulsivity represent useful conceptualizations that involve dissociable cognitive functions, which are mediated by neuroanatomically and neurochemically distinct components of cortico-subcortical circuitry. The constructs were historically viewed as diametrically opposed, with impulsivity being associated with risk-seeking and compulsivity with harm-avoidance. However, they are increasingly recognized to be linked by shared neuropsychological mechanisms involving dysfunctional inhibition of thoughts and behaviors. In this article, we selectively review new developments in the investigation of the neurocognition of impulsivity and compulsivity in humans, in order to advance our understanding of the pathophysiology of impulsive, compulsive, and addictive disorders and indicate new directions for research.