Differential profile of the CCKB receptor antagonist CI-988 and diazepam in the four-plate test.
The cholecystokininB receptor antagonist CI-988 ([R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1(3,7)]dec-2-yloxy)carbonyl]amino]- propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid compound with 1-deoxy-1-(methylamino)-D-glucitol (1:1)) and the benzodiazepine receptor agonist diazepam were tested for potential anxiolytic effects on punished exploratory behavior in the four-plate test using mice. Diazepam (0.31-5 mg/kg PO) increased the number of shocks taken in a dose-dependent manner, an effect blocked by the benzodiazepine receptor antagonist flumazenil. CI-988 (0.00001-1 mg/kg PO) tended to increase the number of delivered shocks over the chosen dose range; this effect was, however, not dose-related or as large as that produced by diazepam. A limited testing of the 5-hydroxytryptamine3 receptor antagonist ondansetron (0.1 and 1 mg/kg PO) suggested an effect similar to CI-988. These results indicate that distinct and contrasting dose-response profiles exist for these classical and atypical drugs in an animal model of anxiety based on electric shock.
Dooley
D J
DJ
Department of Neuroscience, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, MI 48106-1047.
Klamt
I
I
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy* / Q000523:psychology; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D005106:Exploratory Behavior / Q000187:drug effects; D005442:Flumazenil / Q000494:pharmacology; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008536:Meglumine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D017294:Ondansetron / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*
D014151:Anti-Anxiety Agents; D007211:Indoles; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D005442:Flumazenil; D017294:Ondansetron; D008536:Meglumine; D003975:Diazepam