Anti-aggressive effects of the selective high-efficacy 'biased' 5-HT1A receptor agonists F15599 and F13714 in male WTG rats

BACKGROUND: The serotonin (5-HT) deficiency hypothesis of aggression is being seriously challenged by pharmacological data showing robust anti-aggressive effects of 5-HT1A receptor agonists in dose ranges that concomitantly inhibit 5-HT neurotransmission. Hence, an adequate interpretation of the role of 5-HT activity in regulating aggression depends on elucidating the predominant site of action, i.e., raphe presynaptic autoreceptors versus forebrain postsynaptic heteroreceptors, of these 5-HT1A receptor agonists. OBJECTIVES: The present experiments investigated the anti-aggressive properties of the selective 5-HT1A receptor agonists F15599 that preferentially target postsynaptic 5-HT1A heteroreceptors in the frontal cortex and F13714 that more preferentially activates raphe somatodendritic 5-HT1A autoreceptors. METHODS: Both 'biased' agonists were acutely administered intraperitoneally in aggressive resident male WTG rats confronting an intruder. RESULTS: Systemic administration of F15599 and F13714 exerted very potent (ID50 = 0.095 and 0.0059 mg/kg, respectively) anti-aggressive effects. At 4.5-fold higher dose ranges, the anti-aggressive effects were accompanied by concomitant motor inactivity and/or reduction of social engagement. Pretreatment with WAY-100635 counteracted the behavioural effects of both agonists. CONCLUSIONS: Overall, the qualitatively similar but quantitatively different anti-aggressive profiles of F15599 and F13714 largely correspond to their distinct 5-HT1A receptor binding/activation potencies. Moreover, the marked anti-aggressive potency of F13714 adds additional support for a critical role of raphe somatodendritic 5-HT1A autoreceptors, and hence phasic 5-HT neuron activity, in the initiation/execution of aggressive actions

Untangling the neurobiology of escalated aggression in animals

Canines’ capacity for uncontrolled aggressiveness and violent-like behavior is a serious veterinary medicine concern and inflicts an awful burden on their owners. Unfortunately, the current intervention strategies and treatment options for curbing these problematic behavioral expressions are largely inadequate. Hence, a more fundamental knowledge about the neurobiological determinants of aggression is urgently needed. In particular, the interaction between environmental factors and the neurochemical substrates that causally underlies the shift towards escalated and maladaptive forms of aggressive behavior (e.g., violence) is in great need to be unraveled. Novel experimental laboratory models of violent-like aggression in rodents combined with newly emerging technologies for mapping and manipulating neuronal activity with anatomical, genetic and temporal precision are indispensable to obtain this goal. This contribution presents some of the most significant developments made during the last decade in this understudied preclinical animal research field that promise to significantly advance our understanding of the etiology, brain mechanisms and potential therapeutic interventions of excessive aggressive behaviors

Development of violence in mice through repeated victory along with changes in prefrontal cortex neurochemistry

Recent reviews on the validity of rodent aggression models for human violence have addressed the dimension of pathological, maladaptive, violent forms of aggression in male rodent aggressive behaviour. Among the neurobiological mechanisms proposed for the regulation of aggressive behaviour in its normal and pathological forms, serotonin plays a major role. However, the results on the detailed mechanism are still confusing and controversial, mainly because of difficulties in extrapolating from rodent to human psychopathological behaviour. Our aim was to investigate the involvement of serotonin in pathological aggression. We subjected mice genetically selected for high (SAL, TA, NC900 lines) and low (LAL, TNA, NC100) aggression levels to a repeated resident-intruder experience (RRI mice) or to handling as a control procedure (CTR mice). Pathological aggression parameters we recorded were aggression towards females and lack of communication between the resident and its opponent. In the same mice, we measured the monoamine levels in the prefrontal cortex, a brain region strongly involved in the regulation of motivated behaviour. Our results show that SAL mice augmented their proneness to attack and showed the most pathological phenotype, with disregard of the opponent's sex, high territorial behavioural patterns, and low sensitivity to signals of subordination. In contrast, TA and NC900 augmented their proneness to attack and low discrimination of the opponent's signals, without showing offence towards females. After repeated resident-intruder experience, serotonin levels in the prefrontal cortex were significantly lower in SAL than in LAL whereas dopamine turnover was significantly higher, compared to CTR mice. Serotonin turnover was significantly reduced in all RRI mice, with no strain differences. Noradrenaline was significantly lower in aggressive mice of the TA and NC900 lines compared to their low-aggressive counterparts, with no effect of the repeated resident-intruder experience. We conclude that social experience changes prefrontal cortex neurochemistry and elicits pathologically aggressive phenotypes. (C) 2008 Elsevier B.V. All rights reserved