Vol. 282, Issue 1, 148-161, 1997

S 15535, A Novel Benzodioxopiperazine Ligand of Serotonin (5-HT)_1A Receptors: II. Modulation of Hippocampal Serotonin Release in Relation to Potential Anxiolytic Properties

Mark J. Millan, Stephan Hjorth, Rosario Samanin, Rudy Schreiber¹ , Robert Jaffard, Brigitte De Ladonchamps, Sylvie Veiga, Bertrand Goument, Jean-Louis Peglion, Michael Spedding and Mauricette Brocco

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, France (M.J.M., R.Schreiber, B.D.L., S.V., B.G., J.-L.P., M.S., M.B.), Psychology Department, University Bordeaux I, Avenue des Facultés 33405, Talence Cedex, France (R.J.), Department of Pharmacology, University of Göteborg, Medicinareg, 7, Göteborg, Sweden (S.H.) and Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy (R.Samanin)

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.