S-15535, A NOVEL BENZODIOXOPIPERAZINE LIGAND OF SEROTONIN (5-HT)(1A) RECEPTORS .2. MODULATION OF HIPPOCAMPAL SEROTONIN RELEASE IN RELATION TO POTENTIAL ANXIOLYTIC PROPERTIES

In these studies, we characterized the influence of the novel benzodio xopiperazine serotonin (5-HT)(1A) ligand, S 15535, on the release of 5 -HT in rat hippocampus and compared its potential anxiolytic propertie s with those of the 5-HT1A receptor partial agonist, buspirone, the 5- HT1A 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 1553 5 (3.0) was blocked by WAY 100,635 (0.3), (-)-penbutolol (2.0) and (-) tertatolol (8.0), antagonists at 5-HT1A autoreceptors. In rats, fear-i nduced 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 155 35 (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; bu spirone (0.16-10.0) and, at high doses, DZM (2.5-40.0) were also effec tive. 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 100,63 5 (0.00063-0.63) significantly increased open-arm entries, whereas the y were increased by DZM (0.16-0.63). In the pigeon conflict test, S 15 535 (0.04-0.16 i.m.) markedly increased punished responses and only sl ightly 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 punis hed and decreasing unpunished responses. In the presence of the 5-HT1A antagonist, (-)-alprenolol (10.0 mg/kg i.m.), S 15535 did not increas e punished responses. In a Geller conflict paradigm in rats, S 15535 d ose-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. an d 2.5-40.0 p.o.) exerted little influence on motor behavior. In conclu sion, in line with its net inhibition of serotoninergic transmission b y activation of 5-HT1A autoreceptors and blockade of postsynaptic 5-HT 1A receptors, S 15535 expresses anxiolytic activity. In addition, it d isplays antiaggressive (and antidepressant, accompanying paper) proper ties. Further, S 15535 does not compromise motor behavior at doses ove r which it expresses its anxiolytic properties. Thus, S 15535 represen ts a promising candidate for the treatment of anxious states in man.