Discriminative stimulus properties of midazolam in the pigeon

Five pigeons were trained to discriminate injections of midazolam (1.0 or 3.0 mg/kg i.m.) from saline with responding maintained under a fixed-ratio 30 schedule of food delivery. When other benzodiazepines were tested, they consistently produced greater than 80% of midazolam-appropriate responding. The order of potency for substituting for midazolam was triazolam greater than alprazolam = diazepam = lorazepam greater than midazolam greater than flurazepam = nitrazepam greater than nordiazepam. The barbiturate phenobarbital (10-100 mg/kg) substituted for midazolam in three of four pigeons whereas pentobarbital (1.0-30 mg/kg) substituted in only two of five pigeons. Several nonbenzodiazepine anxiolytics were also evaluated. Methaqualone (3.0-56 mg/kg) substituted in only one of four pigeons and meprobamate (30-100 mg/kg) failed to substitute in any pigeon tested. CL 218,872, when administered either i.m. (0.3-30 mg/kg) or p.o. (1.0-56 mg/kg), and buspirone (0.3-30 mg/kg) did not substitute for midazolam. Compounds from pharmacological classes not related to midazolam also failed to substitute for midazolam. Pretreatment with the benzodiazepine antagonist flumazenil (Ro 15-1788; 0.03-1.0 mg/kg) antagonized the discriminative stimulus properties of midazolam in a dose-related manner in all pigeons tested. However, this antagonism could not be overcome with increasing doses of midazolam in all pigeons. The results of the present study demonstrate that midazolam is an effective discriminative stimulus in the pigeon. Benzodiazepine anxiolytics, but not other compounds with sedative and/or anxiolytic properties, were found to reliably substitute for midazolam. These results suggest that the discriminative stimulus effects of midazolam are pharmacologically selective.