CHARACTERIZATION OF 5-HYDROXYTRYPTAMINE(1A) PROPERTIES OF FLESINOXAN - IN-VIVO ELECTROPHYSIOLOGY AND HYPOTHERMIA STUDY

Flesinoxan is a high affinity and selective 5-hydroxytryptamine(1A) (5-HT1A) ligand which, unlike the 5-HT1A agonists of the azapirone class, does not generate 1-(2-pyrimidinyl)piperazine, an alpha(2)-adrenoreceptor antagonist. In view of potential antidepressant effects of flesinoxan, this study was undertaken to characterize its 5-HT1A properties in the rat brain using in vivo electrophysiology and hypothermia paradigms. The suppressant effect of microiontophoretic applications of flesinoxan on the firing activity of CA(3) pyramidal neurons was blocked by concomitant application of the 5-HT1A antagonist BMY 7378. Compared to gepirone, the efficacy of flesinoxan to suppress the firing activity of CA(3) pyramidal neurons was significantly greater. While the coapplication of flesinoxan antagonized the suppressant effect of 5-HT on CA(3) pyramidal neurons, it failed to do so on dorsal raphe 5-HT neurons, indicating that flesinoxan acts as a partial agonist at postsynaptic and as a full agonist at presynaptic 5-HT1A receptors. The capacity of flesinoxan to antagonize the effect of 5-HT on CA(3) pyramidal neurons was similar to that of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and significantly greater than that of gepirone. The intravenous administration of flesinoxan suppressed the firing activity of both CA(3) pyramidal neurons and dorsal raphe 5-HT neurons. However, when compared to 8-OH-DPAT, significantly higher doses of flesinoxan were required. The acute brain penetration of [H-3]8-flesinoxan and [H-3]8-OH-DPAT was, therefore, determined. Nine minutes after intravenous administration, [H-3]8-OH-DPAT reached significantly greater brain concentration than [H-3]flesinoxan. Subcutaneous administration of flesinoxan and 8-OH-DPAT produced a dose-dependent hypothermia. The flesinoxan-induced hypothermia was significantly attenuated by prior administration of the non-selective 5-HT1A antagonist pindolol and the 5-HT1/2 antagonist methysergide. Similar degrees of hypothermia were achieved with 3 mg/kg of flesinoxan and 0.5 mg/kg of 8-OH-DPAT. The maximal effect of flesinoxan occurred 30 min later than that of 8-OH-DPAT and faded more slowly. The 5-HT1A properties of flesinoxan suggest that it may be an effective anxiolytic/antidepressant agent.