Differences in Anxiolytic-Like Profile of Two Novel Nonbenzodiazepine BZ (ϖ) Receptor Agonists on Defensive Behaviors of Mice

Abstract

The present experiments compared the behavioral effects of two novel BZ (ϖ) receptor agonists, the pyridazinone Y-23684 (1–30 mg/kg) and the pyrido[1,2-a]benzimidazole RWJ-46771 (0.01–0.3 mg/kg) with the BZs diazepam (0.5–3 mg/kg) and clobazam (1–30 mg/kg) in the mouse defense test battery (MDTB), a model for the screening of anxiolytic drugs. In the MDTB, Swiss mice were confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken during and after rat confrontation were flight, risk assessment, defensive threat/attack, and escape attempts. Results showed that clobazam and Y-23684 significantly modified all defense responses in the presence of the rat at doses that did not decrease spontaneous locomotor activity. These drugs decreased avoidance reactions after the rat was introduced into the runway, reduced flight speed and risk assessment activities of mice chased by the rat, increased risk assessment displayed when subjects were constrained in a straight alley, and reduced defensive threat and attack behaviors upon forced contact. Diazepam significantly decreased all but one (number of avoidances when the rat was first introduced into the runway) defensive behaviors. RWJ-46771 reduced risk assessment in the chase test, avoidance responses, flight speed, and defensive threat and attack reactions, but these effects occurred in the great part at motor-impairing doses, suggesting that the decrease in defensiveness may have been contaminated by behavioral suppression. Finally, following the removal of the rat from the runway, only Y-23684 reduced escape behavior at doses that did not decrease spontaneous behavior. Taken together, these findings demonstrate that Y-23684 displayed anxiolytic-like activity comparable to that of BZs in the MDTB. Although RWJ-46771 significantly modified most defensive behaviors, the effects may have been confounded by decreases in locomotor activity.