Behavioural pharmacology of benzodiazepines.

Acute injections of benzodiazepines produce sedative effects in the rat that can be detected by decreases in spontaneous motor activity and exploration. The effects are found with low doses, are dose-related and correlate well with plasma concentrations. With repeated daily doses there is tolerance to the sedative effects within 3-5 days even with benzodiazepines with short half-lives and no active metabolites. In the rat there may be some pharmacokinetic tolerance accounting for some of the behavioural tolerance, but pharmacokinetic changes cannot explain the tolerance to low doses of chlordiazepoxide. With chronically treated rats there is no relationship between plasma benzodiazepine concentrations and sedation. There is rapid recovery from tolerance to the sedative effects and if the animals are tested undrugged there is no detectable effect 24 h after the last dose. Anxiolytic effects emerge after a few days of benzodiazepine treatment, but after 10-20 days of treatment there is tolerance to these effects in the social interaction test and in the corticosterone-stress response.