CHARACTERIZATION OF THE BEHAVIORAL PROFILE OF THE NON PEPTIDE CRF RECEPTOR ANTAGONIST CP-154,526 IN ANXIETY MODELS IN RODENTS - COMPARISON WITH DIAZEPAM AND BUSPIRONE

The present series of experiments compared the behavioral effects of t he novel non-peptide CRF antagonist CP-154,526 with those of diazepam and the 5-HT1A receptor partial agonist buspirone in classical animal models of anxiety including conflict tests (punished lever pressing an d punished drinking tests in rats) and exploratory models (elevated pl us-maze test in rats, light/dark choice and free-exploration tests in mice), and a recently developed mouse defense test battery (MDTB) whic h has been validated for the screening of anxiolytic drugs. Results fr om both conflict procedures showed that diazepam (2.5-10 mg/kg, IF) pr oduced clear anxiolytic-like effects, whereas buspirone (2.5 mg/kg, IF ) displayed anticonflict activity in the punished drinking test only. CP-154,526 (0.6-20 mg/kg) was devoid of significant activity in both p rocedures. In the elevated plus-maze, diazepam (2 mg/kg, IF) produced significant effects on traditional (i.e. spatio-temporal) and ethologi cally derived (i.e. risk assessment and directed exploration) indices of anxiety. Buspirone (1-4 mg/kg, IF) reduced risk assessment activiti es only, and CP-154,526 (0.6-20 mg/kg, IF) did not modify the indices of anxiety in the elevated plus-maze. In the light/dark test, diazepam (2.5-5 mg/kg, IF) and CP-154,526 (10-40 mg/kg, IF) affected all behav ioral indices of anxiety, while buspirone reduced risk assessment acti vities at the highest doses only (10 and 15 mg/kg, IF). In the free-ex ploration test, diazepam (1 mg/kg, IF) reduced avoidance responses tow ards novelty, as indicated by the increase in exploratory activity in a novel compartment and the decrease in risk assessment. CP-154,526 fa iled to affect the former behavior and weakly reduced the latter (5' a nd 20 mg/kg, IF). Buspirone (1.25-5 mg/kg, IF) was inactive in this te st. Finally, in the MDTB, diazepam (0.5-3 mg/kg, IF) attenuated all de fensive reactions of mice confronted with a rat stimulus (i.e. flight, risk assessment and defensive attack) or with a situation associated with this threat (i.e. contextual defense). Buspirone (1.25-5 mg/kg, I F) reduced defensive attack and contextual defense, while CP-154,526 ( 5-20 mg/kg, IF) affected all defensive behaviors, with the exception o f one risk assessment measure. The finding that CP-154,526 displayed p ositive effects in mice but not in rats may be due to increased sensit ivity to environmental stress of the strains used (i.e. BALB/c, Swiss) and/or to the fact that animals were exposed to unavoidable stress st imuli which may lead to a significant activation of the CRF system. Al though in mice the anxiety-reducing potential of CP-154,526 is superio r to that of the atypical anxiolytic buspirone, it is smaller in terms of the magnitude of the effects and the number of indices of anxiety affected than that of diazepam.