FAILURE OF CCK RECEPTOR LIGANDS TO MODIFY ANXIETY-RELATED BEHAVIORAL SUPPRESSION IN AN OPERANT CONFLICT PARADIGM IN RATS

The effects of cholecystokinin (CCK) receptor ligands were studied in the rat safety signal withdrawal conflict procedure, an operant paradigm sensitive to both anxiolytic and anxiogenic compounds. In this procedure, behavioural suppression of lever pressing for food was induced by the withdrawal of a conditioned signal for safety without the usual presentation of a conditioned signal for danger. The compounds tested were selective CCK-B antagonists [CI-988 (0.01-1 mg/kg SC), L-365,260 (0.0042 mg/kg IF) and LY 262,691 (0.001-1 mg/kg SC)], CCK-B agonists [CCK-4 (0.01-1 mg/kg SC) and BC 264 (0.004-2 mg/kg IP)] and CCK-A antagonists [devazepide (0.001-1 mg/kg SC) and lorglumide (0.01-1 mg/kg SC)]. None of these drugs induced the expected behavioural effects, i.e. an anxiolytic-like release of the behavioural suppression with CCK-B and, possibly, CCK-A antagonists and/or a further reduction of lever pressing with CCK-B agonists, indicative of an anxiogenic-like potential. In contrast, the established anxiolytic lorazepam (0.06-0.25 mg/kg IP), as well as diazepam (2 mg/kg IP) and buspirone (0.25mg/kg SC) used as positive control drugs, released the suppression of pressing for food during the period associated with the safety signal withdrawal, whereas picrotoxin(1 mg/kg IF), used as an anxiogenic control, further reduced responding during this conflict period. The present results contrast with a series of published data suggesting the involvement of CCK processes in anxiety-related behaviour in rodent models such as the elevated plus-maze or the light:dark two compartment test, and in panic disorders in humans. They indicate that the behavioural effects of one category of drugs might vary considerably, depending on the experimental situation. Furthermore, they allow the conclusion that anticipatory anxiety generated by withdrawal of conditioned signals for safety does not involve CCK-related processes.