A model of 'antipredator' defense in Swiss-Webster mice: effects of benzodiazepine receptor ligands with different intrinsic activities.

A mouse defense test battery (MDTB) has been designed to assess defensive reactions of Swiss-Webster mice to situations associated with nonpainful threat. When compared to mice approached by a leather glove, animals confronted with an anesthetized or a conscious rat displayed potentiated flight responses and defensive threat/attack reactions, while risk assessment performances were generally similar in all three conditions. Furthermore, escape attempt responses following removal of the stimulus were higher in the conscious rat condition compared to the two other groups. Taken together, these results suggest that flight reactions and defensive threat/attack responses are specific to the rat, and thus indicate that the MDTB may relate to 'antipredator' defense. In mice confronted with an anaesthetized rat, administration of the benzodiazepine (BZ) receptor full agonist chlordiazepoxide (5-25mg/kg, i.p., 30min) and the BZ partial agonist Ro 19-8022 (0.5-2mg/kg, i.p., 30min) altered one of two risk assessment measures and inhibited defensive attack behaviors, but failed to counter the post-predator increase in escape attempts. In addition, Ro 19-8022 also strongly reduced flight responses. The overall behavioral profile suggests a fear/anxiety-reducing action of both drugs. By contrast, administration of the BZ inverse agonist Ro 19-4603 (0.025-0.1mg/kg, i.p., 30min) reliably released these defensive responses. Interestingly, the BZ antagonist flumazenil (5-20mg/kg, i.p., 30min) manifested differential intrinsic activity depending upon the level of threat. Thus, in a weakly threatening situation, the drug potentiated flight reactions, indicating an inverse agonist-like action, decreased defensive biting in a highly threatening situation, indicating an agonist activity. These findings demonstrated that BZ ligands differently modulated 'antipredator' defense in Swiss-Webster mice, depending upon their intrinsic (positive or negative) efficacy, but also depending upon the defense strategy required by the threat.