Ex vivo binding of flibanserin to serotonin 5-HT1A and 5-HT2A receptors

Flibanserin has been repotted to be an agonist at 5-HT1A-receptors and an a ntagonist at 5-HT(2A)receptors, with higher affinity fur 5-HT1A receptors. Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects, flibanserin was shown to exert 5-HT2A antagonism at doses (4-5 mg kg(-1)) that are lower or equal to thos e required to stimulate 5-HT1A receptors. In order to understand this pheno menon, the interaction of flibanserin with 5-HT1A and 5-HT2A receptors was evaluated in ex vivo binding studies. This interaction was evaluated in the prefrontal cortex, hippocampus and midbrain by using [H-3]8-OH-DPAT and [H -3]ketanserin to label 5-HT1A and 5-HT2A receptors, respectively. Flibanser in was given at 1, 10 and 30 mg kg(-1) intraperitoneally. The dose of 1 mg kg(-1) displaced both radioligands preferentially in the frontal cortex. Th e doses of 10 and 30 mg kg(-1) reduced the binding of both radioligands in all the three brain regions non-selectively by about 50% and 70%, respectiv ely. The displacement was maximal after 0.5 h and was reduced or not eviden t after 3 h. We conclude that 5-HT2 antagonism brought about by low doses o f flibanserin may reflect functional mechanisms more than receptor-mediated effects. (C) 2001 Academic Press.