In vivo electrophysiological assessment of the agonistic properties of flibanserin at pre- and postsynaptic 5-HT1A receptors in the rat brain

✍ Scribed by Lynne E. Rueter; Claude De Montigny; Pierre Blier

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 251 KB
• Volume: 29
• Category: Article
• ISSN: 0887-4476
• DOI: 10.1002/(sici)1098-2396(199808)29:4<392::aid-syn11>3.0.co;2-t

✦ Synopsis

Flibanserin (BIMT 17) has been described as a 5-HT 1A agonist with preferential affinity for postsynaptic 5-HT 1A receptors and as a 5-HT 2A antagonist. Indeed, using the forskolin-stimulated cAMP accumulation technique, flibanserin but not the 5-HT 1A agonists buspirone and 8-OH-DPAT had agonistic activity at postsynaptic 5-HT 1A receptors in the cerebral cortex. The present in vivo electrophysiological study investigated the agonistic properties of this novel compound in pre-and postsynaptic areas of the anesthetized rat brain using local microiontophoretic application and systemic administration. The inhibition induced by either local or intravenous administration of flibanserin was current-and dose-dependent. Based on the ability of 5-HT 1A antagonists to block or reverse the inhibitory action of the compound, the effect of flibanserin was shown to be mediated via 5-HT 1A receptors. In addition, as determined by the concurrent microiontophoretic application of flibanserin and 5-HT, flibanserin behaved as a full agonist in the dorsal raphe nucleus (DRN) and the medial prefrontal cortex (mPFC), but as a partial agonist in the CA 3 region of the hippocampus. Based on neuronal responsiveness observed with the local microiontophoretic application of flibanserin, it was found that the agonist was most potent on 5-HT 1A receptors in the hippocampus, followed by the mPFC and DRN (I T 50 values: 260, 1,260, and 1,365 nanocoulombs, respectively). However, based on the ED 50 values obtained from intravenous administration of the drug, flibanserin was most potent in the DRN followed by the hippocampus and mPFC (ED 50 values: 239, 1,414, and 2,984 µg/kg, respectively). Therefore, flibanserin presented a marked selectivity for postsynaptic 5-HT 1A receptors when applied locally, but not when administered intravenously. It remains to be determined if flibanserin preferentially activates postsynaptic 5-HT 1A receptors upon sustained systemic administration.