Mechanism of action of flibanserin in the learned helplessness paradigm in rats

The mechanism of action of flibanserin, a 5-HT 1A receptor agonist and a 5-HT 2A receptor antagonist, was investigated in learned helplessness in rats. The effect of flibanserin (32 mg/kg, i.p. 30 min before testing) on learned helplessness was not antagonized by the (a) 5-HT synthesis inhibitor parachlorophenylalanine (pCPA; 150 mg/kg p.o.×3 times), which reduced brain 5-HT by 89%; (b) 5-HT 1A receptor antagonists (±)- N- tert-butyl-3-4-(2-ethoxyphenyl)piperazin-1yl-2-phenyl propionamide [WAY100135; 10 mg/kg, i.p. 30 min before flibanserin, or 40 mg/kg, s.c. 15 min before flibanserin] and tertatolol (2.5 and 5 mg/kg, i.p. 30 min before flibanserin); and (c) 5-HT 2 receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg, s.c. simultaneously with flibanserin). The effect of flibanserin on learned helplessness was antagonized by the dopamine D 1 receptor antagonist [ R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SCH 23390; 0.1 mg/kg, i.p. 30 min before flibanserin) and by the opioid receptor antagonist naloxone (3 mg/kg, s.c. 15 min before flibanserin). Flibanserin (32 and 64 mg/kg) did not induce conditioned place preference. In conclusion, flibanserin improved rats' performance in the learned helplessness paradigm, by stimulating dopamine D1 and opioid receptors, probably indirectly, since flibanserin has a low affinity for these receptors.