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The effects of RO 15-4513, RO 15-3505 and FG 7142 on the anxiolytic properties of ethanol in mice were investigated using the plus-maze test of anxiety. Before being tested on the plus-maze, the mice were tested in a holeboard apparatus. All three inverse agonists attenuated the reduction in exploration caused by ethanol in the holeboard test. In the plus-maze, only RO 15-4513 and FG 7142, which possess anxiogenic properties when administered alone, attenuated ethanol's anxiolytic effect. which alone has no effect on anxiety, failed to significantly reduce ethanol's anxiolytic effects. Neither RO 15-4513 nor FG 7142 reduced the increase in the total number of arm entries caused by ethanol. These data indicate that the interaction between ethanol and benzodiazepine receptor ligands depends both on the intrinsic properties of the ligands and the behavior under investigation.

The behavioral effects of two highly selective alpha2-adrenoceptor antagonists, atipamezole and idazoxan, were investigated in mice using the plusmaze test of anxiety and the holeboard test of directed exploration and locomotor activity. No anxiogenic effect, as assessed by the tendency to enter the closed as opposed to open arms of the plusmaze, was noted for either drug at any dose tested. Neither were there any significant effects on locomotor activity or directed exploration (head-dipping) in the holeboard, or total plusmaze arm entries at any dose of either drug. The co-administration of either atipamezole or idazoxan had no effect on either the anxiolytic effect of ethanol (2 g/kg) or its locomotor stimulant effect in the holeboard. Atipamezole (1.0 and 3.0 mg/kg) significantly reversed the ethanol-induced reduction in exploratory head-dipping; a similar trend was seen for idazoxan. There was also a significant potentiation of the ethanol-induced increase in the number of total arm entries made on the plusmaze caused by 1.0 mg/kg (but not 3.0 mg/kg) atipamezole and both 0.3 and 1.0 mg/kg idazoxan. The results suggest that some of the behavioral effects of ethanol can be reversed by alpha2-adrenoceptor antagonists whilst others are unchanged.

The intrinsic effects of the benzodiazepine receptor inverse agonists RO 15-4513 and FG 7142 on the behavior of mice in a holeboard were investigated. Both drugs caused dose-related decreases in exploratory head-dipping. The highest dose of FG 7142 (40 mg/kg) also reduced locomotor activity. RO 15-4513 (1.5 and 3.0 mg/kg) and FG 7142 (10 and 20 mg/kg) reversed the reductions in the number of head-dips caused by ethanol (2 g/kg). The higher doses of these two drugs also partially reversed the locomotor stimulant action of ethanol. Animals that received ethanol in combination with either inverse agonist spent less time head-dipping than vehicle-treated controls. These data indicate that FG 7142 and RO 15-4513 can reverse, at least in part, some of the behavioral effects of ethanol. Neither drug significantly altered blood alcohol concentrations suggesting that the antagonism does not result from pharmacokinetic changes.