The effects of compounds varying in selectivity as 5-HT(1A) receptor antagonists in three rat models of anxiety.
Compounds varying in selectivity as 5-HT(1A) receptor antagonists have recently been reported to produce benzodiazepine-like antianxiety effects in mice. To assess the cross-species generality of these findings, the present experiments compared the effects of diazepam (0.625-5 mg/kg) with those of several non-selective (MM-77, 0.03-1 mg/kg and pindobind-5-HT(1A), 0.1-5 mg/kg) and selective (WAY100635, 0.01-10 mg/kg, p-MPPI, 0.01-3 mg/kg and SL88.0338, 0.3-10 mg/kg) 5-HT(1A) receptor antagonists in three well-validated anxiolytic screening tests in rats: punished lever-pressing, punished drinking, and the elevated plus-maze. In the punished lever-pressing conflict test, none of the 5-HT(1A) receptor antagonists modified rates of punished responding, whereas in the punished drinking test, WAY100635 (0.3-1 mg/kg), SL88.0338 (3-10 mg/kg), p-MPPI (1 mg/kg), MM-77 (0.03-0.3 mg/kg), but not pindobind-5-HT(1A), produced clear anticonflict activity. However, the increase in punished responding with the 5-HT(1A) compounds was smaller than that produced by diazepam, indicating weaker anxiolytic-like activity. In the elevated plus-maze test, WAY100635 (0.1-0.3 mg/kg), SL88.0338 (0.3-10 mg/kg), MM-77 (0.01-3 mg/kg), pindobind-5-HT(1A) (0.1-3 mg/kg), but not p-MPPI, showed anxiolytic-like activity on traditional behavioral indices, increasing the percentage of time spent in open arms and the percentage of open arm entries. As was the case in the punished drinking test, the magnitude of the positive effects of the 5-HT(1A) compounds was generally smaller than that of diazepam. Of the ethological measures recorded in the plus-maze, all compounds markedly decreased risk assessment (i.e. attempts) over the entire dose-range, but only diazepam clearly increased directed exploration (i.e. head-dipping). Although the present results demonstrate that 5-HT(1A) receptor antagonists elicit anxiolytic-like effects in rats, this action appears to be test-specific and, unlike previous findings in mice, smaller than that observed with benzodiazepines. The data are discussed in relation to the possible relevance of species differences in 5-HT(1A) receptor function and the nature of the anxiety response studied.
Griebel
G
G
Sanofi-Synthélabo, 31 Avenue Paul Vaillant-Couturier, 92220, Bagneux, France. guy.griebel@sanofi-synthelabo.com
Rodgers
R J
RJ
Perrault
G
G
Sanger
D J
DJ
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D000081005:Cyclohexane Monoterpenes; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D010869:Pindolol / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013388:Succinimides / Q000494:pharmacology
D000631:Aminopyridines; D000081005:Cyclohexane Monoterpenes; D007546:Isoquinolines; C413583:MM 77; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; C413584:SL 88.0338; D012702:Serotonin Antagonists; D013388:Succinimides; C084712:pindobind; C087205:4-(2'-methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-iodobenzamido)ethyl)piperazine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010869:Pindolol; D003975:Diazepam