S-15535, A NOVEL BENZODIOXOPIPERAZINE LIGAND OF SEROTONIN (5-HT)(1A) RECEPTORS .1. INTERACTION WITH CLONED HUMAN (H)5-HT1A, DOPAMINE HD(2) HD(3) AND H-ALPHA(2A)-ADRENERGIC RECEPTORS IN RELATION TO MODULATION OF CORTICAL MONOAMINE RELEASE AND ACTIVITY IN MODELS OF POTENTIAL ANTIDEPRESSANT ACTIVITY/

The novel, potential anxiolytic, S15535 (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, d opamine (DA) and NAD simultaneously determined in single samples of th e frontal cortex (FCX) of freely moving rats, and compared its activit y 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-HT1A receptors (K-i = 0. 7 nM) and >250-fold lower affinity at cloned hD(2) (400 nM), hD(3) (24 8 nM) and h alpha(2A)-adrenergic (AR) (190 nM) receptors. S 15535 (0.0 8-5.0 mg/kg s.c.) markedly and dose-dependently suppressed dialysate l evels of 5-HT in the FCX, nucleus accumbens and striatum of freely mov ing 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 NA D in the FCX were dose-dependently increased by S 15535, and this effe ct was mimicked by fluoxetine. The influence of S 15535 and fluoxetine on FCX levels of DA was regionally specific inasmuch as dialysate lev els of DA in the accumbens and striatum were not modified. The selecti ve 5-HT1A antagonist, WAY 100,635 ethoxyphenyl)-1-piperazinyl]ethyl}-N -(2-pyridinyl) cyclohexanecarboxamide (0.16) transiently elicited a sl ight increase in cortical levels of 5-HT, an action opposite to that o f S 15535. Further, in the presence of WAY 100,635 (0.16), the influen ce of S 15535 (0.63) on cortical levels of 5-HT, DA and NAD was marked ly attenuated. Upon chronic administration of S 15535 or fluoxetine (1 0.0 mg/kg s.c. daily for 14 days, in each case), there was no signific ant alteration in the density of beta-AR receptors in the FCX. However , in contrast to fluoxetine, S 15535 elicited a significant (25%) decr ease in the density (B-max) of 5-HT2A receptors labeled by [H-3]ketans erin in the cortex; there was no alteration in K-d. In a learned helpl essness paradigm in rats, S 15535 (0.63-40.0 mg/kg p.o.) markedly redu ced escape deficits on each of three consecutive days of testing. Fluo xetine (2.0-8.0 mg/kg i.p.) was also active in each session, but prese nted a biphasic dose-response curve. Finally, under the conditions use d, neither S 15535 (0.63-10.0) nor fluoxetine (0.63-10.0) decreased im mobility time in the forced swim test. In conclusion, S 15535 is a sel ective ligand of cloned, h5-HT1A receptors. Its agonist actions at 5-H T1A autoreceptors underlie its ability to decrease extracellular level s of 5-HT in the FCX, and likely contribute to the increase in extrace llular levels of DA and NAD evoked by S 15535 in this structure. Furth er, S 15535 is active in several other, although not all, models of po tential AD activity. Thus, although S 15535 is under development as an anxiolytic agent, a further characterization of its putative AD actio ns would be of interest.