INDUCTION OF TOLERANCE TO AND PHYSICAL-DEPENDENCE ON PENTOBARBITAL CONTINUOUS INTRACEREBROVENTRICULAR ADMINISTRATION

A new model of barbiturate tolerance and dependence was developed usin g i.c.v. infusion of pentobarbital. Male Harlan Sprague-Dawley rats we ighing 250 to 300 were implanted with i.c.v. cannulae and infused with sodium pentobarbital (500 mug/10 mul/hour) for 6 days. The pentobarbi tal-infused group had a shorter duration of pentobarbital-induced loss of righting reflex than the saline-infused group. When i.c.v. pentoba rbital- and saline-infused rats were injected with sodium pentobarbita l (60 mg/kg i.p.), the time course of pentobarbital levels in the seru m and in the brain were not significantly different. The infusion of p entobarbital also did not induce hepatic drug-metabolizing enzymes. Th e depth of thiopental-induced hypothermia was decreased by i.c.v. pent obarbital infusion. During the course of the infusion, the basal body temperature of the pentobarbital-infused rats did not change. Two days after the infusion was discontinued, the basal body temperature was e levated. The increase in body temperature lasted for 8 days. Twenty-fo ur hours after the infusion was discontinued, the pentobarbital-infuse d rats had a significantly shorter onset of t-butylbicyclophosphorothi onate (TBPS)-induced convulsions. These studies show that i.c.v. infus ion can be used to induce pentobarbital tolerance and dependence. This model has the advantage that issues related to induction of hepatic d rug-metabolizing enzymes are eliminated, and it may be useful in the s tudy of barbiturate addiction.