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

• Published in: Pharmacological research 2001-02, Vol.43 (2), p.179-183
• Main Authors: Scandroglio, A, Monferini, E, Borsini, F
• Format: Article
• Language: English
• Subjects: 8-Hydroxy-2-(di-n-propylamino)tetralin - metabolism; Animals; Benzimidazoles - metabolism; Brain - metabolism; Dose-Response Relationship, Drug; Ketanserin - metabolism; Male; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Serotonin Antagonists - metabolism; Serotonin Receptor Agonists - metabolism
• ISSN: 1043-6618
• DOI: 10.1006/phrs.2000.0762

Flibanserin has been reported to be an agonist at 5-HT1A-receptors and an antagonist at 5-HT2A receptors, with higher affinity for 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 those required to stimulate 5-HT1A receptors. In order to understand this phenomenon, 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 [3H]8-OH-DPAT and [3H]ketanserin to label 5-HT1A and 5-HT2A receptors, respectively. Flibanserin 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. The 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%, respectively. The displacement was maximal after 0.5 h and was reduced or not evident after 3 h. We conclude that 5-HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor-mediated effects.