Phenobarbital tolerance and physical dependence: chronically equivalent dosing model.

A rat model of phenobarbital tolerance and physical dependence has been developed based on the 'maximally tolerable, chronically equivalent' dosing paradigm. Sodium phenobarbital was administered orally twice daily for 35 days in individually adjusted doses to achieve mean daily peak CNS depression culminating in severe ataxia. Dose to dose continuity of CNS depression was maintained throughout treatment. At the time of dosing rats were mildly ataxic. Following abrupt termination of chronic treatment, an abstinence syndrome characterized by CNS hyperexcitability was observed, which demonstrates physical dependence. Signs, which included motor, autonomic, and behavioral manifestations, appeared from 12-24 h and animals recovered by 12 days. Although tolerance development was nearly complete on day 10 of treatment, the abstinence syndrome observed was more severe following 35 than after 10 days of chronic treatment. Characteristics of tolerance and physical dependence are similar to those described for other species including humans.