Electrophysiological examination of the effects of sustained flibanserin administration on serotonin receptors in rat brain

1 5-HT1A receptor agonists have proven to be effective antidepressant medic ations, however they suffer from a significant therapeutic lag before depre ssive symptoms abate. Flibanserin is a 5-HT1A receptor agonist and 5-HT2A r eceptor antagonist developed to possibly induce a more rapid onset of antid epressant action through its preferential postsynaptic 5-HT1A receptor agon ism. 2 Flibanserin antagonized the effect of microiontophoretically-applied DOI in the medial prefrontal cortex (mPFC) following 2 days of administration, indicating antagonism of postsynaptic 5-HT2A receptors. This reduction in t he effect of locally-applied DOI was no longer present following 7-day flib anserin administration. 3 Two-day flibanserin administration only marginally reduced the firing act ivity of dorsal raphe (DRN) 5-HT neurons. Following 7 days of administratio n, 5-HT neuronal firing activity had returned to normal and the somatodendr itic 5-HT1A autoreceptors were desensitized. 4 The responsiveness of postsynaptic 5-HT1A receptors located on CA(3) hipp ocampus pyramidal neurons and mPFC neurons, examined using microiontophoret ically-applied 5-HT and gepirone, was unchanged following a 7-day flibanser in treatment. 5 As demonstrated by the ability of the 5-HT1A receptor antagonist WAY 1006 35 to selectively increase the firing of hippocampal neurons in 2- and 7-da y treated rats, flibanserin enhanced the tonic activation of postsynaptic 5 -HT,A receptors in this brain region. 6 The results suggest that flibanserin could be a therapeutically useful co mpound putatively endowed with a more rapid onset of antidepressant action.