Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: Role of 5-HT 1A receptors

1. Using in vivo intracerebral microdialysis in conscious, freely moving rats, we examined the effect of flibanserin, a potential antidepressant drug with high affinity for human 5-HT _1A receptors and four-50-fold lower affinity for 5-HT _2A and D ₄ receptors, on basal extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA) and noradrenaline (NA) in selected regions of the rat brain. 2. Flibanserin at 3 and 10 mg kg ^-1 significantly reduced extracellular 5-HT in the prefrontal cortex (by 30 and 45%) and dorsal raphe (35 and 44%), but had no effect on extracellular 5-HT in the ventral hippocampus. The 3 and 10 mg kg ^-1 doses raised extracellular NA to a similar extent in the prefrontal cortex (47 and 50%). In all, 10 mg kg ^-1 raised extracellular DA in the prefrontal cortex (63%) whereas 3 mg kg ^-1 had no significant effect. 3. Pretreatment with the selective 5-HT _1A receptor antagonist WAY100,635 (0.3 mg kg ^-1) 30 min before 10 mg kg ^-1 flibanserin completely antagonized the latter's effects on extracellular 5-HT, DA and NA in the prefrontal cortex. WAY100,635 by itself had no effect on cortical extracellular monoamines. 4. The results show that the stimulation of 5-HT _1A receptors plays a major role in the effect of flibanserin on brain extracellular 5-HT, DA and NA.