Behavioral studies with anxiolytic drugs. I. Interactions of the benzodiazepine antagonist Ro 15-1788 with chlordiazepoxide, pentobarbital and ethanol.

Lever pressing by squirrel monkeys was maintained under two behavioral procedures known to be sensitive to anxiolytic drugs. Under one procedure, responding maintained by food was suppressed by electric shock (punishment). Under a second procedure, responding was maintained under a multiple schedule in which the first response after 5 min produced either food or shock depending on the stimulus that was present throughout the interval (fixed-interval schedule). Under the punishment schedule, chlordiazepoxide (1.0-100 mg/kg), pentobarbital (1.0-17.0 mg/kg) and ethanol (0.5-2.5 g/kg) increased responding. The benzodiazepine antagonist, Ro 15-1788 (1.0-10.0 mg/kg), which was without behavioral activity when given alone, reversed the effects of chlordiazepoxide in a dose-dependent manner. Ro 15-1788 did not antagonize the effects of pentobarbital or ethanol but potentiated the rate-increasing effects of these compounds. Under the multiple fixed-interval food- or shock-presentation schedule, both chlordiazepoxide and pentobarbital increased responding maintained by food but only decreased responding maintained by shock. Ro 15-1788 antagonized the rate-increasing effects of chlordiazepoxide under the food schedule and reversed the rate-decreasing effects during the shock-presentation schedule; pentobarbital effects were not altered by Ro 15-1788. Certain dose-combinations of chlordiazepoxide and Ro 15-1788 produced large increases in responding maintained by shock, an effect not seen with either drug alone. These studies indicate that Ro 15-1788 antagonizes the behavioral effects of benzodiazepines selectively but not those of other sedative-hypnotic drugs. These results also suggest that Ro 15-1788 may exert certain actions of its own or may unmask other drug effects when given in combination with benzodiazepine and nonbenzodiazepine compounds.