Differentiating benzodiazepine- and barbiturate-like discriminative stimulus effects of lorazepam, diazepam, pentobarbital, imidazenil and zaleplon in two- versus three-lever procedures

Previous studies found that animals trained to discriminate pentobarbital show a relatively inclusive generalization profile. They generalize to sedative-hypnotics and anxiolytics, regardless of differences among such drugs in molecular mechanism of action. In contrast, animals trained to discriminate lorazepam have shown a generalization profile that appears selective for compounds with in-vitro profiles as full agonists at the benzodiazepine modulatory site. The present study investigated whether benzodiazepine receptor ligands, to which pentobarbital-trained rats had generalized under a two-lever procedure, would occasion pentobarbital- or lorazepam-appropriate responding when the rats were retrained to discriminate among pentobarbital, lorazepam and the no-drug condition under a three-lever procedure. A second group of rats was trained first to discriminate lorazepam and then retrained under the same three-lever procedure. Under the two-lever procedure, all pentobarbital-trained rats showed dose-dependent generalization to lorazepam, but not all lorazepam-trained rats showed full generalization to pentobarbital. Both groups showed full generalization to diazepam and zaleplon, a novel hypnotic that is selective for alpha(1)-subunit-containing subtypes of the gamma-aminobutyric acid (GABA)(A) receptor. Pentobarbital-trained rats, but not all lorazepam-trained rats, generalized to imidazenil, Under the three-lever procedure, dose-dependent generalization to lorazepam and pentobarbital was demonstrated on the appropriate levers. Diazepam shared discriminative effects with pentobarbital, zaleplon shared discriminative effects with lorazepam, and imidazenil shared discriminative effects with lorazepam and pentobarbital. These results show that when the opportunity for finer differentiation of discriminative effects of GABAergic drugs is provided, a generalization profile more in line with differential in-vitro profiles can be revealed. (C) 2000 Lippincott Williams & Wilkins.