CCK RECEPTOR ANTAGONISTS IN ANIMAL-MODELS OF ANXIETY - COMPARISON BETWEEN EXPLORATION TESTS, CONFLICT PROCEDURES AND A MODEL-BASED ON DEFENSIVE BEHAVIORS

The present experiments compared the behavioural effects of one cholec ystokinin(A) (CCKA; lorglumide) and two CCKB (PD 135,158 and LY 288513 ) receptor antagonists in classical animal models of anxiety, includin g conflict tests (punished lever pressing and Vogel drinking tests in rats) and exploratory models (elevated plus-maze test in rats and ligh t/dark choice test in mice), and a recently developed mouse defence te st battery (MDTB) which has been validated for the screening of both a nti-panic and classical anxiolytic (i.e. benzodiazepines) drugs. Diaze pam was used as a positive control. Results showed that all three CCK receptor antagonists were inactive in both conflict tests. Furthermore , despite the incorporation of more ethologically-derived measures (i. e. risk assessment activities or directed exploration, or both) no eff ects were observed in the elevated plus-maze and in the light/dark tes ts. These profiles contrast with that of diazepam which displayed clea r anxiolytic-like effects in these models. In the MDTB, the CCK recept or antagonists failed to modify parameters (i.e. risk assessment, defe nsive threat/attack and escape attempts), which have been shown to be particularly sensitive to drugs effective in the treatment of generali zed anxiety. By contrast, the CCKB receptor antagonists PD 135,158 (0. 001-0.01, 1 mg/kg, i.p.) and LY 288513 (1 and 3 mg/kg, i.p.) significa ntly decreased avoidance distance when the rat was first placed in the test apparatus, an effect which is consistent with an anti-panic-like action. Overall, these findings support the idea that classical anima l models of anxiety may not be suitable for evaluation of the behaviou ral effects of CCK receptor antagonists, whereas tests which may model certain aspects of human panic such as the MDTB appear to be more rel iable tools when screening such compounds.