The vicious cycle towards violence: focus on the negative feedback mechanisms of brain serotonin neurotransmission

Abstract

Violence can be defined as a form of escalated aggressive behavior that is expressed out of context and out of inhibitory control, and apparently has lost its adaptive function in social communication. Little is known about the social and environmental factors as well as the underlying neurobiological mechanisms involved in the shift of normal adaptive aggression into violence. In an effort to model the harmful acts of aggression and violence in humans, we recently (re)developed an animal model that is focused on engendering uncontrolled forms of maladaptive aggressive behavior in laboratory-bred feral rats and mice. We show that certain (8–12%) constitutionally aggressive individuals gradually develop, over the course of repetitive exposures to victorious social conflicts, escalated (short-latency, high-frequency and ferocious attacks), persistent (lack of attack inhibition by defeat/submission signals and perseverance of the aggressive attack-biting bout), indiscriminating (attacking female and anesthetized male intruders) and injurious (enhanced vulnerable-body region attacks and inflicted wounding) forms of offensive aggression. Based on the neurobiological results obtained using this model, a revised view is presented on the key role of central serotonergic (auto)regulatory mechanisms in this transition of normal aggression into violence.

The neurobiology of offensive aggression: Revealing a modular view

“…For example, in the feral wild-type Groningen rats a clear positive correlation was found between the level of normal functional forms of aggressiveness and basal CSF concentrations of 5-HT and its metabolite 5-HIAA [144]. Moreover, local tissue as well as micro-dialysate levels of 5-HT and 5-HIAA in for example the frontal cortex did not differ significantly between high-and low-aggressive animals, although there was a slight tendency for lower levels in high aggressive animals [130]. However, this negative correlation between aggression and frontal cortical 5-HT levels became highly significant upon inclusion of samples from the abnormal and excessively aggressive trained fighter animals (Fig.…”

“…Indeed, several studies in our wild-type rats and artificially selected SAL and LAL mice show a widespread central nervous differentiation between the high and low aggressive extremes, for example at the level of the oxytocinergic modulation of the central nucleus of the amygdala [199], the vasopressinergic neurons in the bed nucleus of the stria terminalis and its innervation (density) of the lateral septum [128] and the suprachiasmatic nucleus [129], the auto-inhibitory control of serotonin neurotransmission [130], and striatal dopaminergic mechanisms [131]. Hence, these may be considered as a suite of correlated neurobiological trait characteristics, which in concert may determine the appropriate behavioral and physiological response to environmental challenges.…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…The impulsive and hyperaggressive behaviour of Tph2 2/2 mice resembles the increased defensiveness reported for Pet1 KO [17] and Tph2 R439H mutants [19]. Acute treatment with 5-HT 1A and 5-HT 1B receptor agonists (or 5-HT 2A/2C antagonists) via their inhibitory action on neurotransmission (pre-synaptically or post-synaptically) was reported to reduce aggressive behaviour, and it was suggested that low 5-HT levels in the brain are associated with maladaptive forms of excessive violence rather than with natural defensiveness [3]. Because 5-HT deficiency is likely to result in impaired inhibition of engagement and sustainment of aggressive behaviour, it may explain that Tph2 2/2 mice display exaggerated aggressive behaviour as a consequence of the failure of 5-HT-mediated inhibitory control, thus rendering these mice inept to acquire the abilities of social adjustment.…”

“…The dichotomy between an impulsive-reactive-hostile-affective subtype and a controlled-proactive-instrumentalpredatory subtype has emerged as the most promising construct of qualitatively distinct subtypes of human aggression [2]. In animal models, violence is defined as a form of escalated aggressive behaviour that is expressed out of context and inhibitory control, with a loss of adaptive function in social communication [3,4]. Individual differences in the temperamental traits of impulsivity and aggressiveness, and the ultimate behavioural consequences (such as distinct types of aggression, violence and self-injurious behaviour, including suicidality and addiction) are relatively enduring and continuously distributed as well as substantially heritable, and therefore are likely to result from additive or non-additive interaction of multiple genetic variations with environmental influences.…”

Neuromodulation of the agonistic behavior in two species of weakly electric fish that display different types of aggression

“…For example, the differential involvement of 5-HT in different behavioral phenotypes within a same species has been reported in lizards and mice (Summers et al, 2005b;Caramaschi et al, 2008;de Boer et al, 2009). However, no attempts to identify distinct patterns of activation of the serotonergic system among different types of aggression have been reported so far.…”