Experimental induction of benzodiazepine tolerance and physical dependence.

To initiate studies of benzodiazepine tolerance and physical dependence, a reproducible animal model has been developed utilizing chlordiazepoxide in rats. Based on the "chronically equivalent" dosing principle, a regimen has been devised to maintain rats in a state of quantifiable intoxication for 5 weeks. Chlordiazepoxide was delivered intragastrically on a b.i.d. basis in doses individually adjusted day-to-day and animal-to-animal to produce an equivalent impairment of motor function evaluated by a gross neurological screen. Quantitative analysis of central nervous system depression ratings during the time of peak effect (4 hr postdose) confirmed that the criterion of chronic equivalence was indeed met. Over the 5-week period of repeated dosing, tolerance was reflected in a 5-fold increase in maintenance dose, from 163.3 mg/kg on day 2 to 839.3 mg/kg on day 35. Tolerance developed more rapidly during the first 9 to 10 days, but continued to develop thereafter more slowly without apparent ceiling. Upon abrupt withdrawal, a syndrome of hyperexcitation developed. Signs included twitches, tremors, muscle hypertonus, arched back, piloerection, myoclonic jerks, augmented struggle and vocalization upon handling, increased startle response, tail erection, teeth chatter, blanched ears and weight loss. No spontaneous convulsions occurred. Latency to onset of withdrawal ranged from 2 to 5 days, and signs peaked in intensity in 8 days and disappeared by 14 days posttreatment. This animal model appears to provide a useful tool for the study of specific mechanisms underlying benzodiazepine tolerance and physical dependence.