Abstract
BackgroundThe 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.ObjectivesThe 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.MethodsBoth ‘biased’ agonists were acutely administered intraperitoneally in aggressive resident male WTG rats confronting an intruder.ResultsSystemic 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.ConclusionsOverall, 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.
Highlights
Ever since the initial discoveries that serotonin (5-hydroxytryptamine, 5-HT) serves as a neurotransmitter in the brain (Brodie et al 1955) and that reduced levels of this indolamine were found to be associated with aggressiveness in mice (Maas 1962; Valzelli and Garattini 1968). this evolutionary ancient and extremely well-conserved neurotransmitter system is generally considered the primary molecular orchestrator of aggressive behavioural traits in virtually every animal species, including man
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
This indicates that the autoregulatory negative feedback mechanism may obscure a simple linear relationship between aggression and 5-HT neurotransmission, and that a proper interpretation of the role of serotonin in regulating aggression depends on elucidating the predominant site of action of these 5-HT receptor agonists
Summary
Ever since the initial discoveries that serotonin (5-hydroxytryptamine, 5-HT) serves as a neurotransmitter in the brain (Brodie et al 1955) and that reduced levels of this indolamine (and/or its metabolite 5-hydroxyindole acetic acid, 5-HIAA) were found to be associated with aggressiveness in mice (Maas 1962; Valzelli and Garattini 1968). this evolutionary ancient and extremely well-conserved neurotransmitter system is generally considered the primary molecular orchestrator of aggressive behavioural traits in virtually every animal species, including man (see Duke et al 2013 and de Boer et al 2015 for review). Agonists of 5-HT1A subtype receptors are among the most potent drugs to suppress the initiation and execution of offensive aggressive behavioural displays in various vertebrate species ranging from fish, rodents, guinea pigs, canines to primates, including man (see de Boer and Koolhaas 2005 and Takahashi et al 2012 for review and relevant Citations). This anti-aggressive effect only corroborates the 5-HT deficiency hypothesis of aggression under the assumption that these agonists would mainly act on the postsynaptic 5-HT1A heteroreceptor population, i.e. mimicking higher 5-HT activity. 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
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