cp-154526 and Anxiety-Disorders

The present series of experiments compared the behavioral effects of the 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 and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats, light/dark choice and free-exploration tests in mice), and a recently developed mouse defense test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that diazepam (2.5-10 mg/kg, i.p.) produced clear anxiolytic-like effects, whereas buspirone (2.5 mg/kg, i.p.) displayed anticonflict activity in the punished drinking test only. CP-154,526 (0.6-20 mg/kg) was devoid of significant activity in both procedures. In the elevated plus-maze, diazepam (2 mg/kg, i.p.) produced significant effects on traditional (i.e. spatio-temporal) and ethologically derived (i.e. risk assessment and directed exploration) indices of anxiety. Buspirone (1-4 mg/kg, i.p.) reduced risk assessment activities only, and CP-154,526 (0.6-20 mg/kg, i.p.) did not modify the indices of anxiety in the elevated plus-maze. In the light/dark test, diazepam (2.5-5 mg/kg, i.p.) and CP-154,526 (10-40 mg/kg, i.p.) affected all behavioral indices of anxiety, while buspirone reduced risk assessment activities at the highest doses only (10 and 15 mg/kg, i.p.). In the free-exploration test, diazepam (1 mg/kg, i.p.) reduced avoidance responses towards novelty, as indicated by the increase in exploratory activity in a novel compartment and the decrease in risk assessment. CP-154,526 failed to affect the former behavior and weakly reduced the latter (5 and 20 mg/kg, i.p.). Buspirone (1.25-5 mg/kg, i.p.) was inactive in this test. Finally, in the MDTB, diazepam (0.5-3 mg/kg, i.p.) attenuated all defensive 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.p.) reduced defensive attack and contextual defense, while CP-154,526 (5-20 mg/kg, i.p.) affected all defensive behaviors, with the exception of one risk assessment measure. The finding that CP-154,526 displayed positive effects in mice but not in rats may be due to increased sensitivity to environmental stress of the strains used (i.e. BALB/c, Swiss) and/or to the fact th

Topics: Animals; Anti-Anxiety Agents; Anxiety Disorders; Behavior, Animal; Buspirone; Diazepam; Male; Mice; Mice, Inbred BALB C; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptors, Corticotropin-Releasing Hormone