Vol. 282, Issue 1, 132-147, 1997

S 15535, A Novel Benzodioxopiperazine Ligand of Serotonin (5-HT)_1A Receptors: I. Interaction with Cloned Human (h)5-HT_1A, Dopamine hD₂/hD₃ and h_2A-Adrenergic Receptors in Relation to Modulation of Cortical Monoamine Release and Activity in Models of Potential Antidepressant Activity

Mark J. Millan, Adrian Newman-Tancredi, Jean-Michel Rivet, Mauricette Brocco, Pierre Lacroix, Valérie Audinot, Laetitia Cistarelli and Alain Gobert

Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department (M.J.M., A.N.-T., J.-M.R., M.B., V.A., L.C., A.G.), Croissy-sur-Seine, and Biotrial S.A. (P.L.), Rennes, France

The novel, potential anxiolytic, S 15535 (4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine), is an agonist and antagonist (weak partial agonist) at pre- and postsynaptic serotonin (5-HT)_1A receptors, respectively. Herein, we characterized its influence on dialysate levels of 5-HT, dopamine (DA) and NAD simultaneously determined in single samples of the frontal cortex (FCX) of freely moving rats, and compared its activity in several other models of potential antidepressant (AD) properties with those of the 5-HT reuptake inhibitor (SSRI), fluoxetine. S 15535 displayed high affinity at cloned human (h) 5-HT_1A receptors (K_i = 0.7 nM) and >250-fold lower affinity at cloned hD₂ (400 nM), hD₃ (248 nM) and h_2A-adrenergic (AR) (190 nM) receptors. S 15535 (0.08-5.0 mg/kg s.c.) markedly and dose-dependently suppressed dialysate levels of 5-HT in the FCX, nucleus accumbens and striatum of freely moving rats, whereas fluoxetine (10.0 mg/kg s.c.) elevated levels of 5-HT in each structure. In contrast to 5-HT, dialysate levels of DA and NAD in the FCX were dose-dependently increased by S 15535, and this effect was mimicked by fluoxetine. The influence of S 15535 and fluoxetine on FCX levels of DA was regionally specific inasmuch as dialysate levels of DA in the accumbens and striatum were not modified. The selective 5-HT_1A antagonist, WAY 100,635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide (0.16) transiently elicited a slight increase in cortical levels of 5-HT, an action opposite to that of S 15535. Further, in the presence of WAY 100,635 (0.16), the influence of S 15535 (0.63) on cortical levels of 5-HT, DA and NAD was markedly attenuated. Upon chronic administration of S 15535 or fluoxetine (10.0 mg/kg s.c. daily for 14 days, in each case), there was no significant alteration in the density of -AR receptors in the FCX. However, in contrast to fluoxetine, S 15535 elicited a significant (25%) decrease in the density (B_max) of 5-HT_2A receptors labeled by [³H]ketanserin in the cortex; there was no alteration in K_d. In a learned helplessness paradigm in rats, S 15535 (0.63-40.0 mg/kg p.o.) markedly reduced escape deficits on each of three consecutive days of testing. Fluoxetine (2.0-8.0 mg/kg i.p.) was also active in each session, but presented a biphasic dose-response curve. Finally, under the conditions used, neither S 15535 (0.63-10.0) nor fluoxetine (0.63-10.0) decreased immobility time in the forced swim test. In conclusion, S 15535 is a selective ligand of cloned, h5-HT_1A receptors. Its agonist actions at 5-HT_1A autoreceptors underlie its ability to decrease extracellular levels of 5-HT in the FCX, and likely contribute to the increase in extracellular levels of DA and NAD evoked by S 15535 in this structure. Further, S 15535 is active in several other, although not all, models of potential AD activity. Thus, although S 15535 is under development as an anxiolytic agent, a further characterization of its putative AD actions would be of interest.