Abstract

In these studies, we characterized the influence of the novel benzodioxopiperazine serotonin (5-HT)_1A ligand, S 15535, on the release of 5-HT in rat hippocampus and compared its potential anxiolytic properties with those of the 5-HT_1A receptor partial agonist, buspirone, the 5-HT_1A antagonist, WAY 100,635 and the benzodiazepine, diazepam (DZM). (Doses are in milligrams per kilogram s.c., unless otherwise specified.) S 15535 dose-dependently (0.3–3.0) reduced dialysate concentrations of 5-HT in the hippocampus of anesthetized rats. This action of S 15535 (3.0) was blocked by WAY 100,635 (0.3), (−)-penbutolol (2.0) and (−)-tertatolol (8.0), antagonists at 5-HT_1A autoreceptors. In rats, fear-induced ultrasonic vocalizations (USVs) were dose-dependently abolished by S 15535 (0.16–2.5 s.c. and 0.63–10.0 p.o.), an action mimicked by buspirone (0.02–2.5) and DZM (0.16–10.0). Further, the action of S 15535 (0.63) was abolished by WAY 100,635 (0.16) and (−)-penbutolol (10.0), which were inactive alone. S 15535 dose-dependently (0.63–10.0 s.c. and 2.5–40.0 p.o.) blocked aggressive encounters in isolated mice; buspirone (0.16–10.0) and, at high doses, DZM (2.5–40.0) were also effective. WAY 100,635 (0.16), which was inactive alone, fully antagonized the antiaggressive actions of S 15535 (2.5). In an elevated plus-maze, neither S 15535 (0.0025–10.0), buspirone (0.0025–10.0) nor WAY 100,635 (0.00063–0.63) significantly increased open-arm entries, whereas they were increased by DZM (0.16–0.63). In the pigeon conflict test, S 15535 (0.04–0.16 i.m.) markedly increased punished responses and only slightly decreased unpunished responses, even at a 64-fold higher dose. In contrast, buspirone (0.16–2.5 i.m.) and DZM (0.04–2.5 i.m.) showed no or a less marked (4-fold) separation between doses increasing punished and decreasing unpunished responses. In the presence of the 5-HT_1A antagonist, (−)-alprenolol (10.0 mg/kg i.m.), S 15535 did not increase punished responses. In a Geller conflict paradigm in rats, S 15535 dose-dependently (0.3–3.0) increased punished responses, and its action (1.0) was blocked by (−)-penbutolol (8.0). S 15535 (0.63–40.0 s.c. and 2.5–40.0 p.o.) exerted little influence on motor behavior. In conclusion, in line with its net inhibition of serotoninergic transmission by activation of 5-HT_1A autoreceptors and blockade of postsynaptic 5-HT_1A receptors, S 15535 expresses anxiolytic activity. In addition, it displays antiaggressive (and antidepressant, accompanying paper) properties. Further, S 15535 does not compromise motor behavior at doses over which it expresses its anxiolytic properties. Thus, S 15535 represents a promising candidate for the treatment of anxious states in man.