title: Anti-aggressive effects of the selective high-efficacy 'biased' 5-HT₁A receptor agonists F15599 and F13714 in male WTG rats.
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.
  
  
  OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Sietse F
authors.initials: SF
authors.lastname: de Boer
authors.affiliation: Neurolixis Inc., Dana Point, CA, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Newman-Tancredi
mesh_terms: D000374:Aggression / Q000187:drug effects*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D009474:Neurons / Q000187:drug effects; D010879:Piperazines; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines; D011743:Pyrimidines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects*; D051381:Rats; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*
chemical_list: C119079:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methyl-6-methylaminopyridin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; C524188:3-chloro-4-fluorophenyl-(4-fluoro-4-(((5-methylpyrimidin-2-ylmethyl)amino)methyl)piperidin-1-yl)methanone; D000631:Aminopyridines; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; D058825:Serotonin 5-HT1 Receptor Agonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
keywords: 5-HT1A; Aggressive behaviour; Autoreceptors; Dorsal Raphe; F13714; F15599; Heteroreceptors; Serotonin