Evaluating The Therapeutic Potential of The Oxytocin System in the Treatment of Impulsive Aggression: A Pre-Clinical Investigation

Abstract

Aggression, the act of hostility with the intent to harm, is present across many different species. Whilst it can be a normal or adaptive behaviour in certain situations, such as to defend oneself or to compete over limited resources, it may become pathological if expressed an inappropriate context, or at a disproportionate level. Despite the high prevalence of aggression across a wide range of psychological disorders, there are a lack of targeted, efficacious and safe pharmacological treatments available. Prior research has examined the role of the neuropeptides oxytocin (OXT) and vasopressin (AVP) in rodent models of aggression which reflect normal or adaptive forms of aggression. As such, the current thesis aimed to evaluate these neuropeptides within a mouse model that is more translatable and clinically relevant to pathological human aggression. Chapter 2 aimed to determine the involvement of the oxytocin receptor (OXTR) and vasopressin V1a receptor (V1aR) within a mouse model of non-territorial, impulsive aggression. The findings suggested that activation of the V1aR is critical for inhibiting hyper-aggressive behaviour and promoting pro-social behaviour. Chapter 3 aimed to determine whether the anti-aggressive effects of a 5-HT1A receptor (5-HT1AR) agonist could be explained by downstream release of OXT. The findings suggested that 5-HT1AR agonist-induced inhibition of aggression does not involve OXT, whereas effects on social contact and grooming do. Overall, the findings suggest that activation of V1aRs inhibit impulsive aggression and promote pro-social behaviour. However, given the poor pharmacokinetic properties of these neuropeptides it is unlikely that they can be used to attain long term clinically relevant outcomes. This highlights the V1aR as a candidate for the development of small molecule therapeutics for the treatment of aggression.