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

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

  • Psychopharmacology (Berl). 2016 Mar;233(6):937-47. doi: 10.1007/s00213-015-4173-x.
Sietse F de Boer 1 Adrian Newman-Tancredi 2
Affiliations

Affiliations

  • 1 Department of Behavioral Physiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, P.O. Box 11103, 9700 CC, Groningen, The Netherlands. s.f.de.boer@rug.nl.
  • 2 Neurolixis Inc., Dana Point, CA, USA.
Abstract

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.

Keywords

5-HT1A; Aggressive behaviour; Autoreceptors; Dorsal Raphe; F13714; F15599; Heteroreceptors; Serotonin.

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