High-dose discrimination training with midazolam: context determines generalization profile.

In previous work, greater differentiation among ligands for the benzodiazepine site was found in rats trained to discriminate among vehicle, 0.32, and 3.2 mg/kg midazolam than in animals trained to discriminate a single midazolam dose from vehicle (i.e., virtually all test drugs occasioned low-dose midazolam-appropriate responding, but most did not occasion high-dose midazolam-appropriate responding even at high test doses). A possibility was that merely training with 3.2 mg/kg-midazolam (not previously studied) would result in greater selectivity than training with lower midazolam doses. In the present study, rats were trained to discriminate 3.2 mg/kg i.p. midazolam from no drug under a two-lever, food-maintained, procedure; and drugs from the previous three-lever studies were tested. Triazolam, bretazenil, clonazepam, lorazepam, midazolam, zolpidem, chlordiazepoxide, pentobarbital, and flurazepam all dose-dependently occasioned >80% responding on the midazolam-appropriate lever in roughly that order of potency. Only triazolam had occasioned midazolam 3.2 mg/kg-appropriate responding in the previous work. The greater differentiation among these drugs in the dose-vs.-dose procedure likely was due to a training dose context rather than to the high training dose per se.