V. Hadrava et al., CHARACTERIZATION OF 5-HYDROXYTRYPTAMINE(1A) PROPERTIES OF FLESINOXAN - IN-VIVO ELECTROPHYSIOLOGY AND HYPOTHERMIA STUDY, Neuropharmacology, 34(10), 1995, pp. 1311-1326
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.