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)-adrenorec eptor antagonist. In view of potential antidepressant effects of flesi noxan, this study was undertaken to characterize its 5-HT1A properties in the rat brain using in vivo electrophysiology and hypothermia para digms. The suppressant effect of microiontophoretic applications of fl esinoxan on the firing activity of CA(3) pyramidal neurons was blocked by concomitant application of the 5-HT1A antagonist BMY 7378. Compare d to gepirone, the efficacy of flesinoxan to suppress the firing activ ity of CA(3) pyramidal neurons was significantly greater. While the co application of flesinoxan antagonized the suppressant effect of 5-HT o n CA(3) pyramidal neurons, it failed to do so on dorsal raphe 5-HT neu rons, indicating that flesinoxan acts as a partial agonist at postsyna ptic and as a full agonist at presynaptic 5-HT1A receptors. The capaci ty of flesinoxan to antagonize the effect of 5-HT on CA(3) pyramidal n eurons was similar to that of 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and significantly greater than that of gepirone. The intra venous administration of flesinoxan suppressed the firing activity of both CA(3) pyramidal neurons and dorsal raphe 5-HT neurons. However, w hen compared to 8-OH-DPAT, significantly higher doses of flesinoxan we re 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 con centration than [H-3]flesinoxan. Subcutaneous administration of flesin oxan and 8-OH-DPAT produced a dose-dependent hypothermia. The flesinox an-induced hypothermia was significantly attenuated by prior administr ation 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 eff ect of flesinoxan occurred 30 min later than that of 8-OH-DPAT and fad ed more slowly. The 5-HT1A properties of flesinoxan suggest that it ma y be an effective anxiolytic/antidepressant agent.