The anxiolytic-like effect of the selective 5-HT6 receptor antagonist SB-399885: the impact of benzodiazepine receptors.
The effect of lesion of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 x 10 mg/kg), and the influence of the benzodiazepine receptor antagonist flumazenil (10 mg/kg) on the anticonflict action of N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885), a selective 5-HT6 receptor antagonist, were investigated in the Vogel conflict drinking test in rats. In addition, the interaction between SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) was evaluated in that test. All the compounds tested were administered intraperitoneally. The anticonflict activity produced by SB-399885 (3 mg/kg) was not modified in p-CA-pretreated rats, but it was totally blocked by flumazenil. Combined administration of non-active doses of SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) produced a pronounced anticonflict effect in rats. The present results suggest that the anticonflict activity of SB-399885 is not conditioned by the integrity of 5-HT neurons, and that benzodiazepine receptors are indirectly involved in its effect, possibly due to a functional interaction between 5-HT6 receptors and the gamma-aminobutyric acid (GABA)/benzodiazepine system.
Wesołowska
Anna
A
Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, Kraków PL 31-343, Poland. wesolow@if-pan.krakow.pl
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003220:Conflict, Psychological; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004597:Electroshock; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007274:Injections, Intraperitoneal; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D010133:p-Chloroamphetamine / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D010879:Piperazines; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D011985:Receptors, Serotonin; C503990:SB 399885; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor; D005442:Flumazenil; D010133:p-Chloroamphetamine; D003975:Diazepam