Divergent pathways mediate 5-HT1A receptor agonist effects on close social interaction, grooming and aggressive behaviour in mice: Exploring the involvement of the oxytocin and vasopressin systems.

BACKGROUND: 5-HT1A receptor (5-HT1AR) abnormalities are implicated in aggression, and there has been considerable interest in developing 5-HT1AR agonists for treating aggression. Endogenous oxytocin (OXT) released upon stimulation of 5-HT1ARs in the hypothalamus mediates at least some of the effects of 5-HT1AR agonists on social behaviour. AIMS: Given 5-HT1AR, OXT receptor (OXTR) and vasopressin V1a receptor (V1aR) agonists can all reduce aggression, the current study aimed to determine whether the anti-aggressive effects of 5-HT1AR stimulation can also be explained by downstream actions at OXTRs and/or V1aRs in a mouse model of non-territorial, hyper-aggressive behaviour. METHODS: Male Swiss mice (N=80) were socially isolated or group housed for six weeks prior to the start of testing. Testing involved placing two unfamiliar weight- and condition-matched mice together in a neutral context for 10 minutes. RESULTS: Social isolation led to a pronounced increase in aggressive behaviour, which was dose-dependently inhibited by the 5-HT1AR agonist 8-OH-DPAT (0.1, 0.3 and 1 mg/kg intraperitoneally (i.p.)), with accompanying increases in close social contact (huddling) and grooming. The effects of 8-OH-DPAT on aggression, huddling and grooming were blocked by pretreatment with a selective 5-HT1AR antagonist (WAY-100635; 0.1 mg/kg i.p.). The anti-aggressive effects of 8-OH-DPAT were unaffected by an OXTR antagonist (L-368,899; 10 mg/kg i.p.), whereas the effects on huddling and grooming were inhibited. Pretreatment with a V1aR antagonist (SR49059; 20 mg/kg i.p.) had no effect. CONCLUSIONS: Our study suggests that stimulation of endogenous oxytocin is involved in the effects of 5-HT1AR activation on close social contact and grooming but not aggression.

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.'