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.x3 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-1H-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.
Borsini
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F
CNS Department, Boehringer Ingelheim Pharma KG, Building J63, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany. Franco.Borsini@bc.boehringer-ingelheim.de
Cesana
R
R
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D004924:Escape Reaction / Q000187:drug effects; D006380:Helplessness, Learned; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013876:Thiophenes
D001562:Benzimidazoles; D010879:Piperazines; D011412:Propanolamines; D044402:Receptor, Serotonin, 5-HT2A; D017447:Receptors, Dopamine D1; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; C081293:WAY 100135; D009270:Naloxone; C098107:flibanserin; C005632:tertatolol