Anti-aggressive effects of the selective high-efficacy ‘biased’ 5-HT(1A) 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-HT(1A) 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-HT(1A) receptor agonists. OBJECTIVES: The present experiments investigated the anti-aggressive properties of the selective 5-HT(1A) receptor agonists F15599 that preferentially target postsynaptic 5-HT(1A) heteroreceptors in the frontal cortex and F13714 that more preferentially activates raphe somatodendritic 5-HT(1A) 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 (ID(50) = 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-HT(1A) receptor binding/activation potencies. Moreover, the marked anti-aggressive potency of F13714 adds additional support for a critical role of raphe somatodendritic 5-HT(1A) autoreceptors, and hence phasic 5-HT neuron activity, in the initiation/execution of aggressive actions.