RO15-4513 ANTAGONIZES THE ANXIOLYTIC EFFECTS OF ETHANOL IN A NONSHOCK CONFLICT TASK AT DOSES DEVOID OF ANXIOGENIC ACTIVITY

RO15-4513 is a partial benzodiazepine inverse agonist that has been reported to antagonize some of the biochemical and neurobehavioral actions of ethanol. However, whether this antagonistic action of RO15-4513 is dependent on the drug exerting its intrinsic (inverse agonist) properties is unclear at present. The purpose of the present study was to examine whether RO15-4513 was capable of antagonizing the anxiolytic effects of ethanol in a nonshock conflict task at doses that, by themselves, do not reveal the compound's intrinsic anxiogenic properties. The consummatory conflict task employed (negative contrast) involves quantifying how animals respond to an abrupt, unexpected reduction in reward (sucrose solution), and is particularly sensitive to the effects of anxiolytic agents, including ethanol. As previously demonstrated, depressed consummatory behavior engendered by reward reduction was significantly alleviated by ethanol (0.75 g/kg). This anxiolytic effect of ethanol, however, was antagonized dose dependently by RO15-4513 (0.1875-3.0 mg/kg). Only the highest dose of RO15-4513 (3.0 mg/kg) showed evidence of further response suppression. Lower doses of RO15-4513 tested did not exert an anxiogenic effect when given alone. Thus the antagonism of EtOH's anxiolytic (contrast-reducing) effects occurred at doses of RO15-4513 (0.375-1.5 mg/kg) that did not exhibit any intrinsic anxiogenic activity. As such, these results suggest that RO15-4513 interacts with the anxiolytic effects of ethanol in a nonadditive fashion in this test situation.