Sex differences in the social motivation of rats: Insights from social operant conditioning, behavioural economics, and video tracking.

BACKGROUND: Social behaviour plays a key role in mental health and wellbeing, and developing greater understanding of mechanisms underlying social interaction-particularly social motivation-holds substantial transdiagnostic impact. Common rodent behavioural assays used to assess social behaviour are limited in their assessment of social motivation, whereas the social operant conditioning model can provide unique and valuable insights into social motivation. Further characterisation of common experimental parameters that may influence social motivation within the social operant model, as well as complementary methodological and analytical approaches, are warranted. METHODS: This study investigated the effects of biological sex, housing condition, and time-of-day, on social motivation using the social operant model. This involved training rats to lever press (FR1) for 60-s access to a social reward (same-sex conspecific stimulus). Subjects were male and female Wistar rats, housed under individual or paired conditions, and sessions were conducted either in the mid-late light phase (ZT6-10) or early-mid dark phase (ZT13-17). A behavioural economics approach was implemented to measure social demand and the influence of stimulus partner sex (same- vs. opposite-sex stimulus) on social operant responding. Additionally, video tracking analyses were conducted to assess the degree of convergence between social appetitive and consummatory behaviours. RESULTS: Biological sex, housing conditions, the interaction between sex and housing, and stimulus partner sex potently influenced social motivation, whereas time-of-day did not. Behavioural economics demonstrated that sex, housing, and their interaction influence both the hedonic set-point and elasticity of social demand. Video analysis of social interaction during social operant sessions revealed that social appetitive and consummatory behaviours are not necessarily convergent, and indicate potential social satiety. Lastly, oestrus phase of female experimental and stimulus rats did not impact social motivation within the model. CONCLUSIONS: Social isolation-dependent sex differences exist in social motivation for rats, as assessed by social operant conditioning. The social operant model represents an optimal preclinical assay that comprehensively evaluates social motivation and offers a platform for future investigations of neurobiological mechanisms underlying sex differences in social motivation. These findings highlight the importance of continued consideration and inclusion of sex as a biological variable in future social operant conditioning studies. Humans are social creatures-our everyday interactions with others and the support this provides play a key role in our wellbeing. For those experiencing mental health conditions, people's motivation to engage with others can wane, which can lead them to withdraw from those who support them. Therefore, to develop better treatment strategies for these conditions, we need to gain a deeper understanding of social motivation. Studying social behaviour in animals can facilitate this investigation of social motivation as it allows for a causal understanding of underlying neurobiology that is not possible in human experiments. An optimal way to study social motivation in animals is using the social operant conditioning model, where rats learn to press a lever that opens a door and allows them to interact with another rat for a short time. This study characterised the social operant model by testing whether sex, housing conditions, time-of-day, and the sex of the stimulus partner influence rats' motivation to seek interaction with another rat. We found that female rats were more socially motivated than males, and that rats living alone were more motivated than those living with another rat; interestingly, this effect of housing affected females more than males. Regardless of sex, rats were more motivated to interact with a rat of the opposite sex. These findings provide insights into sex differences in social motivation in rats and new insights into the social operant model which will help guide future research into social motivation and other mental health conditions.

Quiet wakefulness: the influence of intraperitoneal and intranasal oxytocin on sleep-wake behavior and neurophysiology in rats.

STUDY OBJECTIVES: Exogenous administration of the neuropeptide oxytocin exerts diverse effects on various neurobehavioral processes, including sleep and wakefulness. Since oxytocin can enhance attention to social and fear-related environmental cues, it should promote arousal and wakefulness. However, as oxytocin can attenuate stress, reduce activity, and elicit anxiolysis, oxytocin might also prime the brain for rest, and promote sleep. At present, little research has comprehensively characterized the neuropsychopharmacology of oxytocin-induced effects on sleep-wake behavior and no reconciliation of these two competing hypotheses has been proposed. METHODS: This study explored the effects of oxytocin on sleep-wake outcomes using radiotelemetry-based polysomnography in adult male and female Wistar rats. Oxytocin was administered via intraperitoneal (i.p.; 0.1, 0.3 and 1 mg·kg-1) and intranasal (i.n.; 0.06, 1, 3 mg·kg-1) routes. Caffeine (i.p. and i.n.; 10 mg·kg-1) was administered as a wake-promoting positive control. To ascertain mechanism of action, pretreatment experiments with the oxytocin receptor (OXTR) antagonist L-368,899 (i.p.; 5 mg·kg-1) followed by oxytocin (i.p.; 1 mg·kg-1) were also conducted. RESULTS: In both male and female rats, i.p. oxytocin promoted quiet wakefulness at the cost of suppressing active wakefulness, non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Several i.p. oxytocin-induced sleep-wake effects were mediated by OXTR binding. In contrast, i.n. oxytocin did not alter most sleep-wake outcomes at any dose tested. Both i.p. and i.n. caffeine demonstrated wake-promoting effects. CONCLUSIONS: These findings help reconcile competing hypotheses of oxytocin-induced effects on sleep-wake behavior: i.p. oxytocin promotes quiet wakefulness-a state of restful environmental awareness compatible with both oxytocin's anxiolytic effects and its enhancement of processing complex stimuli.

A systematic review and meta-analysis of animal models of binge eating - Part 1: Definitions and food/drink intake outcomes.

Binge eating involves consuming excessive amounts of food within a discrete period of time and is associated with significant impairments in binge-eating disorder and bulimia nervosa. While research on clinical binge eating has provided valuable aetiological insights, animal models allow for closer examination of environmental, biological, and developmental risk factors. Numerous animal models of binge eating exist and differ widely in operational definitions of bingeing, animal characteristics and methodological parameters. The current review aimed to synthesise the available published evidence on these models. A systematic review of binge definitions in 170 articles found most studies displayed good face validity. Meta-analyses on 150 articles confirmed that the amount of food or drink consumed by animals under binge conditions was larger than that of non-binge conditions across many protocols. The meta-regression revealed species, strain, and sex moderated binge effect size, with the largest effect observed in studies with female animals and mice. Risk of bias assessment identified that improved reporting of allocation, baseline characteristics and outcome assessment is required in future studies.

Sucrose intake by rats affected by both intraperitoneal oxytocin administration and time of day.

RATIONALE: Daily limited access to palatable food or drink at a fixed time is commonly used in rodent models of bingeing. Under these conditions, entrainment may modulate intake patterns. Oxytocin is involved in circadian patterns of intake and, when administered peripherally, reduces sucrose intake. However, oxytocin's effects on intake under limited-access conditions and its potential interaction with entrainment have not been explored. OBJECTIVES: This study examined the role of entrainment on intake patterns, oxytocin's effects on sucrose intakes and locomotor activity and whether oxytocin's effects were mediated by its actions at the oxytocin receptor. METHODS: Sated rats received daily 1-h access to 10% sucrose solution either at a fixed or varied time of day. Rats received intraperitoneal oxytocin (0 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg) prior to sucrose access, and spontaneous locomotor activity was assessed in an open-field test. Rats were then pre-treated with an oxytocin receptor antagonist, L368,899, prior to oxytocin before sucrose access. RESULTS: Intake patterns did not differ between fixed- or varied-time presentations; rats consumed more sucrose solution in the middle as opposed to the early-dark phase. Oxytocin dose-dependently reduced sucrose intakes, but also reduced locomotor activity. There was some evidence of partial blockade of oxytocin-induced sucrose intake reductions by L368,899, but the results were unclear. CONCLUSIONS: Time of day and oxytocin impact sucrose solution intake under daily limited access in rats and the sedative-like effects of oxytocin should be considered in future studies on oxytocin and food intake.

The influence of oxytocin-based interventions on sleep-wake and sleep-related behaviour and neurobiology: A systematic review of preclinical and clinical studies.

The oxytocin (OXT) system has garnered considerable interest due to its influence on diverse behaviours. However, scant research has considered the influence of oxytocin on sleep-wake and sleep-related behaviour and neurobiology. Consequently, the objective of this systematic review was to assess the extant preclinical and clinical evidence for the influence of oxytocin-based interventions on sleep-wake outcomes. The primary search was conducted on 22/7/2020 using six electronic databases; 30 studies (19 preclinical, 11 clinical) were included based on inclusion criteria. Studies were evaluated for risk of bias using the SYRCLE tool and the Cochrane risk of bias tools for preclinical and clinical studies, respectively. Results indicated manipulation of the OXT system can influence sleep-wake outcomes. Preclinical evidence suggests a wake-promoting influence of OXT system activation whereas the clinical evidence suggests little or no sleep-promoting influence of OXT. OXT dose was identified as a likely modulatory factor of OXT-induced effects on sleep-wake behaviour. Future studies are necessary to validate and strengthen these tentative conclusions about the influence of OXT on sleep-wake behaviour.

Acute alcohol exposure dose-dependently alleviates social avoidance in adolescent mice and inhibits social investigation in adult mice.

BACKGROUND: Motivations for alcohol consumption often focus on ethanol's purported prosocial effects: social enhancement and reduction of socially focused anxiety. Despite substantial research supporting prosocial effects, contrary research exists demonstrating alcohol-elicited antisocial and asocial behaviours. Additionally, evidence typically fails to delineate whether alcohol-induced prosocial effects are due to alcohol expectancies or pharmacological actions of ethanol. Studies exploring ethanol's pharmacological effects on social behaviour and factors that modulate apparent contradictory prosocial versus asocial effects are lacking. OBJECTIVES: This study investigated whether factors of age, ethanol dose and social fear modulate ethanol-induced pharmacological effects on sociability and social anxiety-like avoidance. METHODS: Experiments examined the acute effects of ethanol doses (0, 0.25, 0.8, 1.6 g/kg; i.p.) in adult (10-week-old) and adolescent (PND 31-33) C57BL/6J male mice on social interaction using a social fear conditioning paradigm. Control experiments assessed whether ethanol-induced effects were social-specific. RESULTS: In adult mice, no specific effects of ethanol on social avoidance were observed at any dose. However, high-dose ethanol (1.6 g/kg) suppressed social approach in all adult mice. In contrast, low-dose ethanol (0.25 g/kg) alleviated social avoidance in adolescent mice and no social suppression was observed at higher ethanol doses. Thus, higher doses of ethanol impair social behaviour in adult mice, whereas lower doses specifically alleviate social anxiety-like avoidance in adolescent mice. CONCLUSIONS: Age, dose and social fear are critical modulators of acute ethanol-induced pharmacological effects on social behaviour. Inconsistencies in ethanol-induced social consequences appear at least partly mediated by pharmacological interactions-not solely alcohol expectancies.

Oxytocin and vasopressin inhibit hyper-aggressive behaviour in socially isolated mice.

Despite the high prevalence of aggression across a wide range of disorders, there is a severe lack of pharmacological treatments. Recent rodent studies have shown both centrally and peripherally administered oxytocin is effective in reducing territorial aggression, an adaptive form of aggression not reflective of pathological hyper-aggression. The current study tested i.p. administered oxytocin and vasopressin in a model of non-territorial hyper-aggression and examined the involvement of oxytocin receptors (OXTR) and vasopressin V1a receptors (V1aR). Male Swiss mice (N = 160) were either socially isolated or group housed for 6 weeks prior to the commencement of testing; wherein two unfamiliar weight and condition matched mice were placed into a neutral context for 10 min. Socially isolated mice exhibited heightened aggression that was powerfully and dose-dependently inhibited by oxytocin and vasopressin and that was accompanied by dose-dependent increases in close social contact (huddling) and grooming. These anti-aggressive effects of oxytocin were blocked by pre-treatment with a higher dose of selective V1aR antagonist SR49059 (20 mg/kg i.p.), but not a lower dose of SR49059 (5 mg/kg i.p.) or selective OXTR antagonist L-368,899 (10 mg/kg i.p.). This is consistent with a growing number of studies linking a range of effects of exogenous oxytocin to actions at the V1a receptor. Interestingly, the highest dose of the OXTR agonist TGOT (10 mg/kg) also reduced isolation-induced aggression. These results suggest that while activation of the V1a receptor appears critical for the anti-aggressive effects of oxytocin, activation of the oxytocin receptor cannot be excluded. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity.'

Contexts Paired with Junk Food Impair Goal-Directed Behavior in Rats: Implications for Decision Making in Obesogenic Environments.

The high prevalence of obesity and related metabolic diseases calls for greater understanding of the factors that drive excess energy intake. Calorie-dense palatable foods are readily available and often are paired with highly salient environmental cues. These cues can trigger food-seeking and consumption in the absence of hunger. Here we examined the effects of palatable food-paired environmental cues on control of instrumental food-seeking behavior. In Experiment 1, adult male rats received exposures to one context containing three "junk" foods (JFs context) and another containing chow (Chow context). Next, rats were food-deprived and trained to perform instrumental responses (lever-press) for two novel food rewards in a third, distinct context. Contextual influences on flexible control of food-seeking behavior were then assessed by outcome devaluation tests held in the JF, chow and training contexts. Devaluation was achieved using specific satiety and test order was counterbalanced. Rats exhibited goal-directed control over behavior when tested in the training and chow-paired contexts. Notably, performance was habitual (insensitive to devaluation) when tested in the JF context. In Experiment 2 we tested whether the impairment found in the JF context could be ameliorated by the presentation of a discrete auditory cue paired with the chow context, relative to a second cue paired with the JF context. Consistent with the results of Experiment 1, the devaluation effect was not significant when rats were tested in the JF context with the JF cue. However, presenting the chow cue increased the impact of the devaluation treatment leading to a robust devaluation effect. Further tests confirmed that performance in the chow context was goal-directed and that sensory-specific satiety in the JF context was intact. These results show that environments paired with palatable foods can impair goal-directed control over food-seeking behavior, but that this deficit was improved by a cue paired with chow. This has promising implications for assisting individuals in controlling their eating behavior in environments designed to dysregulate it.