Drug discrimination analysis of midazolam under a three-lever procedure: I. Dose-dependent differences in generalization and antagonism.

Twelve rats were trained to discriminate two doses of midazolam, 0.32 and 3.2 mg/kg, from no drug under a three-lever, multiple-trials procedure (15-min time-out, 5-min fixed-ratio-10 schedule of food reinforcement). In tests, midazolam (0.0032-10 mg/kg), administered cumulatively within a session or acutely across sessions, produced dose-dependent increases in responding on the low-dose lever after 0.1 to 1.0 mg/kg and on the high-dose lever at higher doses in all rats. Flumazenil dose-dependently antagonized the discriminative stimulus effect of 3.2 mg/kg of midazolam in all rats but antagonism of the lower midazolam training dose was not obtained in all rats. Pentobarbital dose-dependently produced responding on the levers associated with the no-drug and 0.32-mg/kg midazolam conditions but not on the lever associated with 3.2 mg/kg of midazolam. These results differed from those that would have been predicted from studies in midazolam-trained rats in two-lever procedures. The muscle relaxant methocarbamol and nonsedative/anxiolytic drugs (morphine, caffeine and d-amphetamine) did not produce responding on the lever associated with either the low or high midazolam training dose. However, cocaine produced partial responding on the lever associated with the low midazolam dose. Thus, the discriminative stimulus effects of 3.2 mg/kg of midazolam were benzodiazepine-like and not a function of general sedative or muscle-relaxant effects. The 0.32-mg/kg midazolam training dose, in this context, appeared less specific than 3.2 mg/kg of midazolam. Taken together, the results suggest that not all differences among the training stimuli in this three-lever context reflect simple differences in dose.