Somatodendritic 5-HT1A autoreceptors mediate the anti-aggressive actions of 5-HT1A receptor agonists in rats: An ethopharmacological study with S-15535, alnespirone, and WAY-100635

To elucidate the relative contribution of somatodendritic 5-HT1A autorecept ors and postsynaptic 5-HT1A receptor the specific anti-aggressive propertie s of 5-HT1A receptor agonists, the influence of the novel benzodioxopiperaz ine compound S-15535, which behaves in vivo as a competitive antagonist at postsynaptic 5-HT1A receptors and as an agonist at 5-HT1A autoreceptors, up on offensive and defensive aggression was investigated in wild-type rats us ing a resident-intruder paradigm. S-15535 exerted a potent dose-dependent d ecrease in offensive, but not defensive, aggressive behavior (inhibitory do se (ID)(50) = 1.11 mg/kg). This anti-aggressive profile was roughly similar to that of the potent pre- and postsynaptic 5-HT1A full agonist alnespiron e (ID50 = 1.24). The drug's profound anti-aggressive actions were not accom panied by sedative side effects or signs of the "5HT-(1A) receptor-mediated behavioral syndrome," which are characteristically induced by prototypical 5-HT1A receptor agonists like 8-OH-DPAT and buspirone. The selective pre- and postsynaptic 5-HT1A antagonist WAY-100635, which was inactive given alo ne, abolished the anti-aggressive effects of S-15535 and alnespirone, there by confirming the involvement of 5-HT1A receptors. Furthermore, combined ad ministration of S-15535 and alnespirone elicited an additive anti-aggressiv e effect, providing further support for somatodendritic 5-HT1A receptor inv olvement. Finally, the postsynaptic 5-HT1A antagonistic properties of S-155 35 were confirmed by showing blockade of the alnespirone-induced hypothermi a, a postsynaptic 5-HT1A mediated response in the rat. These data provide e xtensive evidence that the anti-aggressive effects of 5-HT1A receptor agoni sts are expressed via their action on somatodendritic 5-HT1A autoreceptors, thereby most likely attenuating intruder-activated serotonergic neurotrans mission. [Neuropsychopharmacology 23:20-33, 2000] (C) 2000 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. All rights reserved.