Abstract

The present study characterized the effects of the novel, selective, and potent 5-hydroxytryptamine_1A (serotonin) (5-HT_1A) receptor agonist, alnespirone [S-20499, (S)-N-4-[5-methoxychroman-3-yl)propylamino)butyl-8-azaspiro-(4,5)-diacetamide, hydrochloride] on offensive and defensive resident-intruder aggression in wild-type rats and compared its actions with those of the prototypical full 5-HT_1A agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT), the partial 5-HT_1A agonists ipsapirone and buspirone, and the mixed 5-HT_1A/1B agonist eltoprazine. All five agonists exerted effective dose-dependent decreases of offensive aggressive behavior in resident rats; 8-OH-DPAT was the most potent (ID₅₀ = 0.074 mg/kg), followed by eltoprazine (0.24), buspirone (0.72), ipsapirone (1.08), and alnespirone (1.24). However, in terms of selectivity of the antiaggressive effects as determined by the absence of decrements in social interest and general motor activity, alnespirone appeared to be superior. In the defensive aggression test, neither alnespirone nor any of the other four agonists changed defensive behaviors in the intruder rats. The involvement of 5-HT_1A receptors in the antiaggressive actions of these drugs was confirmed by showing that the selective 5-HT_1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride), which was inactive alone, fully prevented the antiaggressive effects of alnespirone, 8-OH-DPAT, and buspirone and partly reversed those of ipsapirone and eltoprazine. The data clearly indicate that alnespirone effectively suppresses offensive aggression with an advantageous profile of action compared with other full or partial 5-HT_1A agonists. These selective antiaggressive actions of alnespirone are mediated by stimulating 5-HT_1Areceptors, presumably the somatodendritic autoreceptors at the raphe nuclei. Furthermore, the data provide evidence for a major involvement of these 5-HT_1A receptors in the modulation of aggressive behavior by 8-OH-DPAT, ipsapirone, buspirone, and eltoprazine.