Behavioral differentiation of benzodiazepine ligands after repeated administration in baboons.

Baboons received repeated daily administration of saline, 5.6 mg/kg midazolam, 5.0 mg/kg flumazenil (Ro15-1788), 3.2 mg/kg 3-carboethoxy-beta-carboline hydrochloride (beta CCE) or 10 mg/kg beta CCE for 5 days. Behavioral signs of sedation and excitation were scored for 1 h after i.m. injections. Daily administration of these benzodiazepine-receptor ligands differentiated their behavioral effects; repeated midazolam resulted in tolerance to the sedative and ataxic effects; repeated beta CCE resulted in sensitization to its convulsant properties; and repeated flumazenil or saline produced no changes in behavior. In a second study, baboons received repeated injections of midazolam (5.6, 11.2 or 20 mg/kg per day) for 6 days. All three groups became tolerant to the sedative and ataxic effects of midazolam. Acute injections of flumazenil (5.0 mg/kg) on day 5 produced a dose-dependent withdrawal syndrome. This flumazenil treatment produced a slight attenuation in the degree of tolerance to midazolam on day 6, suggesting that receptor sensitivity to the benzodiazepine agonist may have partially reset.