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.

Inter-individual variability in habituation of anxiety-related responses within three mouse inbred strains.

Inter-individual variability in behavioral and physiological response has become a well-established phenomenon in animal models of anxiety and other disorders. Such variability is even demonstrated within mouse inbred strains. A recent study showed that adaptive and non-adaptive anxiety phenotypes (measured as habituation and/or sensitization of anxiety responses) may differ within cohorts of 129 mice. This variability was expressed across both anxiety- and activity-related behavioral dimensions. These findings were based however on re-analysis of previously published data. The present study therefore aimed to empirically validate these findings in 129 mice. In addition, we assessed such inter-individuality in two other strains: BALB/c and C57BL/6. Males of three mouse inbred strains (BALB/c, C57BL/6 and 129S2) were behaviorally characterized through repeated exposure to a mild aversive stimulus (modified Hole Board, 4 consecutive trials). Behavioral observations were supplemented with assessment of circulating corticosterone levels. Clustering the individual response trajectories of behavioral and endocrine responses yielded two multidimensional response types of different adaptive value. Interestingly, these response types were displayed by individuals of all three strains. The response types differed significantly on anxiety and activity related behavioral dimensions but not on corticosterone concentrations. This study empirically confirms that adaptive capacities may differ within 129 cohorts. In addition, it extends this inter-individual variability in behavioral profiles to BALB/c and C57BL/6. Whether these two sub-types constitute differential anxiety phenotypes may differ per strain and requires further study.

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.

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.

Altered performance in a rat gambling task after acute and repeated alcohol exposure.

RATIONALE: A bidirectional relationship between alcohol use disorder (AUD) and deficits in impulse control and decision making has been suggested. However, the mechanisms by which neurocognitive impairments predispose to, or result from AUD remain incompletely understood. OBJECTIVES: The aim of this study is to gain more insight in the effects of alcohol exposure on decision making and impulse control. We used two modified versions of the rat gambling task (rGT) that differ in the net gain and the punishment magnitude associated with the different response options. METHODS: In experiment 1, we assessed the effects of acute alcohol treatment (0-0.8 g/kg) on rGT performance. In experiment 2, we determined the effects of alcohol on rGT acquisition (15 sessions, 0.6 g/kg). Next, these animals were challenged with alcohol (0-1.0 g/kg) prior to rGT sessions. RESULTS: Acute alcohol treatment suppressed baseline performance in both rGT versions but only modestly altered decision making. Treatment with alcohol during acquisition increased risky choices in the rGT version that involved larger punishment and blunted the reduction in win-shift behavior during acquisition in both rGT versions. Moreover, rats treated with alcohol during acquisition showed an increase in premature and perseverative responding upon subsequent alcohol challenges (0-1.0 g/kg) and were less sensitive to the behavioral suppressant effects of alcohol. CONCLUSIONS: Our results show that repeated alcohol exposure alters decision making during rGT acquisition and reduces the ability to adjust choice behavior on the basis of feedback. In addition, repeated alcohol exposure unmasks its behavioral disinhibitory effects in the rGT. Impaired responsiveness to choice feedback and behavioral disinhibition may contribute to the development of AUD.

Chromosomal assignment of quantitative trait loci influencing baseline circulating total cholesterol level in male laboratory mice: report of a consomic strain survey and comparison with published results.

BACKGROUND: An important risk for atherosclerosis is a low level of HDL cholesterol. Baseline HDL cholesterol is under complex genetic and environmental control. Here we report on results of male mice from a consomic strain survey and the parental inbred strains for baseline circulating total cholesterol concentration, which is almost the same as HDL cholesterol in chow fed mice. The consomic strains have been derived from C57BL/6J (host strain) and A/J (donor strain) inbred lines. The work contributes to the value of the mouse as an animal model for studying the genetic background of differences in baseline circulating total and HDL cholesterol levels. RESULTS: The consomic strain survey suggested that mouse chromosomes 1, 7, 9, 14, 16, 17, 19, X, and Y contained at least one quantitative trait locus that is involved in baseline circulating total cholesterol concentration. All consomic lines, for which there is evidence that the substituted chromosome contains a quantitative trait locus, increase compared to the host strain baseline circulating total cholesterol concentration. Since there is evidence that 'body weight', 'age at blood sampling', 'time of the day blood was collected', and 'season' influence this phenotype, additional statistical analyses (with these variables as covariates) were performed. Now there is only evidence for quantitative trait loci on chromosomes 1, 8, 12, and Y. Taken the present results together with previous consomic strain surveys there is evidence that all mouse chromosomes carry quantitative trait loci that control baseline circulating total cholesterol levels. There was however little agreement between the present consomic strain results and previous sets of data. This might be explained by seasonal effects and differences in methodological variables such as age of the mice, fasting versus non-fasting, percentage of dietary fat, unanesthetized versus anesthetized mice, and the daily light-dark cycle. CONCLUSIONS: The present findings, when compared with previous consomic strain surveys, clearly illustrate the complexity of the genetic-environmental architecture for the regulation of baseline circulating total cholesterol levels in mice. Different data can be obtained from different labs and it underscores that animal geneticists should present as accurate a picture as possible of the laboratory mouse's environment.

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.

Optimizing the dosing interval of buprenorphine in a multimodal postoperative analgesic strategy in the rat: minimizing side-effects without affecting weight gain and food intake.

Buprenorphine is commonly used as (part of) postoperative analgesic treatment with dosage dependent side-effects such as pica behaviour. No strict consensus exists about the optimal dosing interval of buprenorphine, as its duration of action has been described as being in the range of 6-12 h. In this study, dosing intervals of 8 h (thrice-a-day) and 12 h (twice-a-day) for buprenorphine in a multimodal analgesic strategy (concurrent administration of a non-steroidal anti-inflammatory drug) were compared on food intake, weight and side-effects (gnawing on plastic Petri dishes and growth rate, indicative of pica behaviour) in rats. The food intake and weight of both intervals were comparable, as the animals from the twice-a-day group did not lose more weight or consumed less food during the analgesic period. The rats from the thrice-a-day group suffered from more side-effects, as the growth rate was decreased and more plastic was gnawed on. It is recommended to carefully evaluate analgesic and side-effects when using buprenorphine. When side-effects are observed, the possibility of increasing the dosing interval of buprenorphine should be explored. In this study, increasing the dosing interval of buprenorphine in a multimodal analgesic regimen resulted in reduced unwanted side-effects, without increasing weight loss or decreasing food intake. Although this is suggestive of provision of comparable analgesia, future studies including more pain-related readout parameters to assess the effect of the dosing interval on analgesic efficacy are recommended.