Discriminative stimulus effects of atypical anxiolytics in baboons and rats

Baboons and rats were trained to discriminate lorazepam and pentobarbital in a food-maintained two-lever drug vs. no-drug discrimination procedure. Previous research showed that benzodiazepines, but not barbiturates, occasioned drug lever responding in the lorazepam-trained animals. Lorazepam and six nonbenzodiazepines that have been proposed as anxiolytics (CGS 9896, CL 218,872, PK 9084, zopiclone, buspirone and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) were studied in test sessions in which responding on either level produced food. Of the nonbenzodiazepine compounds studied that displace 3H-benzodiazepines in vitro, CL 218,872 and zopiclone occasioned drug lever responding in all animals; PK 9084 did not occasion drug lever responding in any animal; and CGS 9896 did not occasion drug lever responding in lorazepam- or pentobarbital-trained baboons or in lorazepam-trained rats, but did so in the pentobarbital-trained rats. Buspirone, a nonbenzodiazepine anxiolytic with prominent dopaminergic activity, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, a gamma-aminobutyric acid agonist, also did not occasion drug lever responding in either baboons or rats, regardless of training drug. Time course studies in baboons with CGS 9896, PK 9084, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and buspirone did not reveal delayed onset of drug stimulus generalization. Some differences in potency as a function of route of administration were found with CL 218,872, zopiclone and buspirone. The discriminative stimulus effects of lorazepam, CL 218,872 and zopiclone were antagonized by the benzodiazepine receptor antagonist Ro 15-1788. It is concluded that the discriminative stimulus properties of these nonbenzodiazepine compounds thus do not co-vary with their antipunishment effects, with their clinical efficacy as anxiolytics or with benzodiazepine receptor binding.