Differences in anxiolytic-like profile of two novel nonbenzodiazepine BZ (omega) receptor agonists on defensive behaviors of mice

The present experiments compared the behavioral effects of two novel BZ (om ega) receptor agonists, the pyridazinone Y-23684 (1-30 mg/kg) and the pyrid o[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 w ere confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken during and after rat confrontation wer e flight, risk assessment, defensive threat/attack, and escape attempts. Re sults showed that clobazam and Y-23684 significantly modified all defense r esponses in the presence of the rat at doses that did not decrease spontane ous locomotor activity. These drugs decreased avoidance reactions after the rat was introduced into the runway, reduced flight speed and risk assessme nt activities of mice chased by the rat, increased risk assessment displaye d when subjects were constrained in a straight alley, and reduced defensive threat and attack behaviors upon forced contact. Diazepam significantly de creased 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 an d attack reactions, but these effects occurred in the great part at motor-i mpairing 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 demo nstrate that Y-23684 displayed anxiolytic-like activity comparable to that of BZs in the MDTB. Although RWJ-46771 significantly modified most defensiv e behaviors, the effects may have been confounded by decreases in locomotor activity. (C) 1999 Elsevier Science Inc.