The benzodiazepines: anxiolytic and withdrawal effects.

Benzodiazepine withdrawal, spontaneous or precipitated by the receptor antagonist, flumazenil, produces anxiety that can be measured in animal models. Benzodiazepine inverse agonists also cause anxiety. Their convulsive effects increase after chronic agonist treatment, but they become anxiolytic. Decreases in GABAA receptor sensitivity occur after chronic benzodiazepine treatment. Flumazenil, given 24h prior to the measurements, prevented both the sensitivity changes and benzodiazepine tolerance in vivo. The anxiety and decreases in seizure threshold during withdrawal were also prevented. It has been suggested that flumazenil causes a prolonged 'resetting' of the benzodiazepine receptor complex. Acute flumazenil decreased anxiety-related behaviour during ethanol withdrawal. Concurrent chronic treatment with verapamil completely prevented anxiety following chronic benzodiazepine treatment.