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.
Invernizzi
Roberto William
RW
Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy. rinvernizzi@marionegri.it
Sacchetti
Giuseppina
G
Parini
Stefania
S
Acconcia
Sabrina
S
Samanin
Rosario
R
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004298:Dopamine / Q000737:chemistry* / Q000378:metabolism; D045604:Extracellular Fluid / Q000737:chemistry; D005544:Forecasting; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis / Q000379:methods; D009638:Norepinephrine / Q000737:chemistry* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D017397:Prefrontal Cortex / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011903:Raphe Nuclei / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000737:chemistry* / Q000378:metabolism
D000928:Antidepressive Agents; D001562:Benzimidazoles; D010879:Piperazines; D011725:Pyridines; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; C098107:flibanserin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D004298:Dopamine; D009638:Norepinephrine