Flesinoxan is a high affinity and selective 5-hydroxytryptamine1A (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 CA3 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 CA3 pyramidal neurons was significantly greater. While the coapplication of
flesinoxan antagonized the suppressant effect of
5-HT on CA3 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 CA3 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 CA3 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 [3H]
flesinoxan and [3H]8-
OH-DPAT was, therefore, determined. Nine minutes after
intravenous administration, [3H]8-
OH-DPAT reached significantly greater brain concentration than [3H]
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.