DRUG DISCRIMINATION ANALYSIS OF MIDAZOLAM UNDER A 3-LEVER PROCEDURE .2. DIFFERENTIAL-EFFECTS OF BENZODIAZEPINE RECEPTOR AGONISTS

Twelve rats were trained to discriminate 0.32 and 3.2 mg/kg s.c. midaz olam from no drug under a three-lever, multiple trials drug discrimina tion procedure. In cumulative dose-response tests, midazolam s.c. (0.0 32-10 mg/kg) and i.p. (0.1-10 mg/kg) occasioned dose-dependent increas es first in 0.32 mg/kg (low-dose) lever responding and then in 3.2 mg/ kg (high-dose) lever responding. The benzodiazepines diazepam (0.032-1 8 mg/kg) and triazolam (0.0032-3.2 mg/kg) produced patterns of general ization similar to that of midazolam; however, chlordiazepoxide (0.1-3 2 mg/kg), lorazepam (0.032-10 mg/kg), flurazepam (0.01-10 mg/kg), bret azenil (0.01-32 mg/kg) and the imidazo-pyridazine zolpidem (0.032-3.2 mg/kg) dose-dependently occasioned >80% responding on the low- but not the high-dose midazolam lever. Clonazepam (0.1-10 mg/kg) occasioned 0 % responding on the high-dose lever, but also failed to occasion full generalization to the low-dose midazolam lever in 40% of the rats. Bre tazenil has been well-characterized as a partial benzodiazepine agonis t and zolpidem as benzodiazepine-receptor-subtype selective; the prese nt results are consistent with their partial or selective agonist effe cts in those other paradigms. The differential effects of the classic 1,4 benzodiazepine agonists tested suggest that the discriminative sti mulus effects of these other compounds may be more differentiable than previous drug discrimination studies have suggested. This three-choic e drug discrimination procedure appears to be a useful model for study ing relative intrinsic efficacies of this class of compounds.