IN-VIVO ELECTROPHYSIOLOGICAL ASSESSMENT OF THE AGONISTIC PROPERTIES OF FLIBANSERIN AND PRESYNAPTIC AND POSTSYNAPTIC 5-HT1A RECEPTORS IN THERAT-BRAIN

Flibanserin (BIMT 17) has been described as a 5-HT1A agonist with pref erential affinity for postsynaptic 5-HT1A receptors and as a 5-HT2A an tagonist. Indeed, using the forskolin-stimulated cAMP accumulation tec hnique, flibanserin but not the 5-HT1A agonists buspirone and 8-OH-DPA T had agonistic activity at postsynaptic 5-TH1A receptors in the cereb ral cortex. The present in vivo electrophysiological study investigate d the agonistic properties of this novel compound in pre- and postsyna ptic areas of the anesthetized rat brain using local microiontophoreti c application and systemic administration. The inhibition induced by e ither local or intravenous administration of flibanserin was current- and dose-dependent. Based on the ability of 5-HT1A antagonists to bloc k or reverse the inhibitory action of the compound, the effect of flib anserin was shown to be mediated via 5-HTA1 receptors. In addition, as determined by the concurrent microiontophoretic application of fliban serin and 5-HT, flibanserin behaved as a full agonist in the dorsal ra phe nucleus (DRN) and the medial prefrontal cortex (mPFC), but as a pa rtial agonist in the CA(3) region of the hippocampus. Based on neurona l responsiveness observed with the local microiontophoretic applicatio n of flibanserin, it was found that the agonist was most potent on 5-T H1A 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 ED50 values obtained form intravenous administration of the drug, flibanserin was most potent in the DRN followed by the hippo campus and mPFC (ED50 values: 239, 1,414, and 2,984 mu g/kg, respectiv ely). Therefore, flibanserin presented a marked selectivity for postsy naptic 5-HT1A receptors when applied locally, but not when administere d intravenously. It remains to be determined if flibanserin preferenti ally activates postsynaptic 5-HT1A receptors upon sustained systemic a dministration. Synapse 29:392-405, 1998. (C) 1998 Wiley-Liss, Inc.