Lack of effect of CCKB receptor antagonists in ethological and conditioned animal screens for anxiolytic drugs.
The effects of the CCKB receptor antagonists L-365,260, CI-988 and L-740,093, a new compound with improved bioavailability and CNS penetration, were assessed for anxiolytic-like effects in three rat anxiolytic screens sensitive to benzodiazepines, the elevated plus maze (EPM), conditioned suppression of drinking (CSD) and conditioned emotional response (CER) tests. In the EPM, L-740,093 (0.1-1.0 mg/kg), L-365,260 (0.00001-10.0 mg/kg), and CI-988 (0.01-1.0 mg/kg) did not increase the time spent on the open arms of the maze or the number of entries onto the open arms. In contrast, the benzodiazepine receptor partial agonist, bretazenil (0.3-10.0 mg/kg), significantly increased both the time spent on the open arms and the number of open arm entries. In the CSD and the CER tests, L-740,093 (0.1-1.0 mg/kg) L-365,260 (0.0001-0.1 mg/kg) and CI-988 (0.01-10.0 mg/kg) failed to increase suppression ratios compared to the vehicle-treated control rats, whereas, the benzodiazepine receptor partial agonist FG 8205 (10.0 mg/kg) (CSD) and bretazenil (0.3-3.0 mg/kg) (CER) both significantly increased suppression ratios compared to vehicle-treated control rats. In addition, L-365,260 (1.0-50.0 mg/kg), CI-988 (0.1-10.0 mg/kg) and diazepam (0.1-1.0 mg/kg) were assessed in a squirrel monkey conflict procedure. Although diazepam significantly increased suppressed lever pressing rates, L-365,260 and CI-988 were without effect. The present findings provide little support for the hypothesis that CCKB receptor antagonists have anti-anxiety effects in animals.
Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
G R
GR
Dawson
N M
NM
Rupniak
S D
SD
Iversen
R
R
Curnow
S
S
Tye
K J
KJ
Stanhope
M D
MD
Tricklebank
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D010671:Phenylurea Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; C058121:L 365260; C054626:bretazenil