Tolerance and dependence after chronic administration of clonidine to the rat.

Acute administration of clonidine (10-70 microgram/kg, IP) disrupted operant behavior maintained by a fixed ratio schedule of reinforcement [1]. When chronically administered (100 microgram/kg, IP and 3 microgram/ml in drinking water) tolerance to the behavioral depressant effect developed within a few days and was complete by 14 days. Abrupt termination of drug treatment in tolerant rats resulted in an abstinence reaction which was characterized by suppression of operant performance for as long as one week. These results demonstrated the development of tolerance to and dependence on clonidine in rats. These behavioral observations in rats may be related to rebound hypertension and irritability of patients given this alpha-adrenergic agonist for treatment of hypertension.