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Rationale: Studies employing the Iowa Gambling Task (IGT) demonstrated that areas of the frontal cortex, including the ventromedial prefrontal cortex, orbitofrontal cortex (OFC), dorsolateral prefrontal cortex, and anterior cingulate cortex (ACC), are involved in the decision-making process. However, the precise role of these regions in maintaining optimal choice is not clear., Objectives: We used the rat gambling task (rGT), a rodent analogue of the IGT, to determine whether inactivation of or altered dopamine signalling within discrete cortical sub-regions disrupts decision-making., Methods: Following training on the rGT, animals were implanted with guide cannulae aimed at the prelimbic (PrL) or infralimbic (IL) cortices, the OFC, or the ACC. Prior to testing, rats received an infusion of saline or a combination of baclofen and muscimol (0.125 μg of each/side) to inactivate the region and an infusion of a dopamine D2 receptor antagonist (0, 0.1, 0.3, and 1.0 μg/side)., Results: Rats tended to increase their choice of a disadvantageous option and decrease their choice of the optimal option following inactivation of either the IL or PrL cortex. In contrast, OFC or ACC inactivation did not affect decision-making. Infusion of a dopamine D2 receptor antagonist into any sub-region did not alter choice preference., Conclusions: Online activity of the IL or PrL cortex is important for maintaining an optimal decision-making strategy, but optimal performance on the rGT does not require frontal cortex dopamine D2 receptor activation. Additionally, these results demonstrate that the roles of different cortical regions in cost-benefit decision-making may be dissociated using the rGT.

Rationale: Early social experiences are of major importance for behavioural development. In particular, social play behaviour during post-weaning development is thought to facilitate the attainment of social, emotional and cognitive capacities. Conversely, social insults during development can cause long-lasting behavioural impairments and increase the vulnerability for psychiatric disorders, such as drug addiction., Objectives: The aim of this study was to investigate whether a lack of social experiences during the juvenile and early adolescent stage, when social play behaviour is highly abundant, alters cocaine self-administration in rats., Methods: Rats were socially isolated from postnatal days 21 to 42 followed by re-socialization until adulthood. Cocaine self-administration was then assessed under a fixed ratio and progressive ratio schedule of reinforcement. Next, cue, cocaine and stress-induced reinstatement of cocaine seeking was determined following extinction of self-administration., Results: Early social isolation resulted in an enhanced acquisition of self-administration of a low dose (0.083 mg/infusion) of cocaine, but the sensitivity to cocaine reinforcement, assessed using a dose-response analysis, was not altered in isolated rats. Moreover, isolated rats displayed an increased motivation for cocaine under a progressive ratio schedule of reinforcement. Extinction and reinstatement of cocaine seeking was not affected by early social isolation., Conclusions: Early social isolation causes a long-lasting increase in the motivation to self-administer cocaine. Thus, aberrations in post-weaning social development, such as the absence of social play, enhance the vulnerability for drug addiction later in life.

Rationale: Social factors influence drug abuse. Conversely, drugs of abuse alter social behavior. This is especially pertinent during post-weaning development, when there are profound changes in the social repertoire, and the sensitivity to the positive and negative effects of drugs of abuse is altered., Objectives: This study aimed to provide an overview of our current understanding of the interaction between drugs of abuse and juvenile/adolescent social behavior., Methods: We first provide evidence that a characteristic form of juvenile and adolescent social behavior, i.e., social play behavior, has reinforcing properties and is affected by drugs of abuse. Next, social risk factors for drug use and addiction are described, including antisocial personality traits and early social insults. Last, we discuss research that investigates social influences on drug use, as well as the consequences of perinatal drug exposure on later social interactions., Results: Social play behavior is highly rewarding in laboratory animals, and it is affected by low doses of opioids, cannabinoids, ethanol, nicotine, and psychostimulants. In humans, antisocial personality traits, most prominently in the form of conduct disorder, are a prominent risk factor for drug addiction. Preclinical studies have consistently shown altered sensitivity to drugs as a result of social isolation during post-weaning development. The social environment of an individual has a profound, but complex, influence on drug use, and perinatal drug exposure markedly alters later social interactions., Conclusions: The studies reviewed here provide a framework to understand the interaction between drugs of abuse and adolescent social interaction, at the preclinical and the clinical level.

Social experiences during youth are thought to be critical for proper social and cognitive development. Conversely, social insults during development can cause long-lasting behavioral impairments and increase the vulnerability for psychopathology later in life. To investigate the importance of social experience during the juvenile and early adolescent stage for the development of cognitive control capacities, rats were socially isolated from postnatal day 21 to 42 followed by re-socialization until they reached adulthood. Subsequently, two behavioral dimensions of impulsivity (impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task) and decision making (in the rat gambling task) were assessed. In a separate group of animals, long-lasting cellular and synaptic changes in adult medial prefrontal cortex (PFC) pyramidal neurons were determined following social isolation. Juvenile and early adolescent social isolation resulted in impairments in impulsive action and decision making under novel or challenging circumstances. Moreover, socially isolated rats had a reduced response to enhancement of dopaminergic neurotransmission (using amphetamine or GBR12909) in the 5-CSRTT under challenging conditions. Impulsive choice was not affected by social isolation. These behavioral deficits were accompanied by a loss of sensitivity to dopamine of pyramidal neurons in the medial PFC. Our data show long-lasting deleterious effects of early social isolation on cognitive control and its neural substrates. Alterations in prefrontal cognitive control mechanisms may contribute to the enhanced risk for psychiatric disorders induced by aberrations in the early social environment.

Rationale: The inability to make profitable long-term decisions has been implicated in several psychiatric disorders. There is emerging evidence to support a role for dopamine (DA) in decision making, but our understanding of the role of noradrenaline (NA) and serotonin (5-HT) in decision making, and of possible interactions between the three monoamines, is limited. Moreover, impulsivity has been associated with aberrant decision making, but the underlying mechanisms are incompletely understood., Objective: The purpose of this study is to improve our understanding of the neuropharmacological mechanisms of decision making and impulse control., Methods: We investigated the effects of amphetamine (0.25-1.0 mg/kg) and selective reuptake inhibitors of DA (GBR12909; 2.5-10 mg/kg), NA (atomoxetine; 0.3-3.0 mg/kg), and 5-HT (citalopram; 0.3-3.0 mg/kg) in a rat gambling task (rGT). Since the rGT allows for detection of impulsive action, i.e., premature responding, we also assessed the relationship between decision making and impulsivity., Results: In the rGT, rats developed an optimal choice strategy from the first session onwards. Elevation of endogenous DA or NA levels increased and decreased impulsivity, respectively, but did not alter decision making. However, simultaneous blockade of DA and NA disrupted decision making, reflected by a relative decrease in choice for the advantageous choice options. Increasing 5-HT neurotransmission did not affect decision making or impulsivity., Conclusions: These data suggest important but complementary or redundant roles of DA and NA neurotransmission in decision-making processes based on reward probability and punishment. Moreover, impulse control and decision making in the rGT rely on dissociable mechanisms.

Rationale: High levels of impulsivity are a core symptom of psychiatric disorders such as ADHD, mania, personality disorders and drug addiction. The effectiveness of drugs targeting dopamine (DA), noradrenaline (NA) and/or serotonin (5-HT) in the treatment of impulse control disorders emphasizes the role of monoaminergic neurotransmission in impulsivity. However, impulsive behavior is behaviorally and neurally heterogeneous, and several caveats remain in our understanding of the role of monoamines in impulse control., Objectives: This study aims to investigate the role of DA, NA and 5-HT in two main behavioral dimensions of impulsivity., Methods: The effects of selective DA (GBR12909; 2.5-10 mg/kg), NA (atomoxetine; 0.3-3.0 mg/kg) and 5-HT (citalopram; 0.3-3.0 mg/kg) reuptake inhibitors as well as amphetamine (0.25-1.0 mg/kg) were evaluated on impulsive action in the five-choice serial reaction time task (5-CSRTT) and impulsive choice in the delayed reward task (DRT). In the 5-CSRTT, neuropharmacological challenges were performed under baseline and long intertrial interval (ITI) conditions to enhance impulsive behavior in the task., Results: Amphetamine and GBR12909 increased impulsive action and perseverative responding and decreased accuracy and response latency in the 5-CSRTT. Atomoxetine increased errors of omission and response latency under baseline conditions in the 5-CSRTT. Under a long ITI, atomoxetine also reduced premature and perseverative responding and increased accuracy. Citalopram improved impulse control in the 5-CSRTT. Amphetamine and GBR12909, but not citalopram or atomoxetine, reduced impulsive choice in the DRT., Conclusions: Elevation of DA neurotransmission increases impulsive action and reduces impulsive choice. Increasing NA or 5-HT neurotransmission reduces impulsive action.

Like human children, most young mammals devote a significant amount of time and energy playing together, and social play is fun. Although social play is very pleasurable, it is more than just a frivolous activity: it is crucial for the development of behavioral flexibility, the acquisition of social and cognitive competence, and the maintenance of group cohesion. Social play is a natural reinforcer, and the neurotransmitter systems intimately implicated in the motivational, pleasurable and cognitive aspects of natural and drug rewards, such as opioids, endocannabinoids, dopamine and norepinephrine, play an important modulatory role in the performance of social play. In this review, we address the notion that social play is rewarding, and discuss recent developments in the neuropharmacology of this behavior. This provides a framework to understand how the brain processes social emotions, to make young individuals enjoy social play.

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 inferior performance of DBA/2 mice when compared to C57BL/6 mice in hippocampus-dependent behavioral tasks including contextual fear conditioning has been attributed to impaired hippocampal function. However, DBA/2J mice have been reported to perform similarly or even better than C57BL/6J mice in the passive avoidance (PA) task that most likely also depends on hippocampal function. The apparent discrepancy in PA versus fear conditioning performance in these two strains of mice was investigated using an automated PA system. The aim was to determine whether these two mouse strains utilize different strategies involving a different contribution of hippocampal mechanisms to encode PA. C57BL/6J mice exhibited significantly longer retention latencies than DBA/2J mice when tested 24 h after training irrespective of the circadian cycle. Dorsohippocampal NMDA receptor inhibition by local injection of the selective antagonist DL-2-amino-5-phosphonovaleric acid (AP5, 3.2 microg/mouse) before training resulted in impaired PA retention in C57BL/6J but not in DBA/2J mice. Furthermore, nonreinforced pre-exposure to the PA system before training caused a latent inhibition-like reduction of retention latencies in C57BL/6J, whereas it improved PA retention in DBA/2J mice. These pre-exposure experiments facilitated the discrimination of hippocampal involvement without local pharmacological intervention. The results indicate differences in PA learning between these two strains based on a different NMDA receptor involvement in the dorsal hippocampus in this emotional learning task. We hypothesize that mouse strains can differ in their PA learning performance based on their relative ability to form associations on the basis of unisensory versus multisensory contextual/spatial cues that involve hippocampal processing., (2007 Wiley-Liss, Inc.)

Autoinhibitory serotonin 1A receptors (5-HT(1A)) in dorsal raphé nucleus (DRN) have been implicated in chronic depression and in actions of selective serotonin reuptake inhibitors (SSRI). Due to experimental limitations, it was never studied at single-cell level whether changes in 5-HT(1A) receptor functionality occur in depression and during SSRI treatment. Here we address this question in a social stress paradigm in rats that mimics anhedonia, a core symptom of depression. We used whole cell patch-clamp recordings of 5-HT- and baclophen-induced G-protein-coupled inwardly rectifying potassium (GIRK) currents as a measure of 5-HT(1A)- and GABA(B) receptor functionality. 5-HT(1A)- and GABA(B) receptor-mediated GIRK-currents were not affected in socially stressed rats, suggesting that there was no abnormal (auto)inhibition in the DRN on social stress. However, chronic fluoxetine treatment of socially stressed rats restored anticipatory behavior and reduced the responsiveness of 5-HT(1A) receptor-mediated GIRK currents. Because GABA(B) receptor-induced GIRK responses were also suppressed, fluoxetine does not appear to desensitize 5-HT(1A) receptors but rather one of the downstream components shared with GABA(B) receptors. This fluoxetine effect on GIRK currents was also present in healthy animals and was independent of the animal's "depressed" state. Thus our data show that symptoms of depression after social stress are not paralleled by changes in 5-HT(1A) receptor signaling in DRN neurons, but SSRI treatment can alleviate these behavioral symptoms while acting strongly on the 5-HT(1A) receptor signaling pathway.

The influence of housing temperature in early life on subsequent growth and development of broiler chickens was investigated. Hatchlings were exposed to an ambient temperature of 34 degrees C (NT) or 28 degrees C (LT) on d 1. Both temperature regimes decreased with 1 degrees C per day for 5 d. At d 6 the ambient temperature of the LT group was increased to the same ambient temperature as the NT group. At d 29 all chickens were exposed to 10 degrees C for 7 d. Navel temperature was lower in the LT group than in the NT group from d 2 to 5. Body weight of the chickens was higher in the NT group than in the LT group and the difference between both groups increased in time. Temperature treatment during the early post-hatching period did not result in a long-term alternation in organ development, haematocrit value, energy and protein metabolism or the occurrence of ascites. Although not significantly, the course of metabolism suggested that early thermal treatment had long-term effects. Before cold treatment in week 5, the NT group showed higher values for energy and protein metabolism than the LT group, but during cold exposure, the opposite was found. We concluded that exposure of chickens to a moderate reduction in house temperatures during early post-hatching life seemed to have long-term negative effects on the performance of these chickens, but, on the other hand, it seemed that these chickens were better prepared to withstand cold challenge later in life.