TY - JOUR T1 - Induction of tolerance to and physical dependence on pentobarbital continuous intracerebroventricular administration. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1300 LP - 1305 VL - 266 IS - 3 AU - T Kimura AU - T Miyaoka AU - P A Saunders AU - M L Baker AU - A S Hume AU - I Yamamoto AU - I K Ho Y1 - 1993/09/01 UR - http://jpet.aspetjournals.org/content/266/3/1300.abstract N2 - A new model of barbiturate tolerance and dependence was developed using i.c.v. infusion of pentobarbital. Male Harlan Sprague-Dawley rats weighing 250 to 300 were implanted with i.c.v. cannulae and infused with sodium pentobarbital (500 micrograms/10 microliters/hour) for 6 days. The pentobarbital-infused group had a shorter duration of pentobarbital-induced loss of righting reflex than the saline-infused group. When i.c.v. pentobarbital- and saline-infused rats were injected with sodium pentobarbital (60 mg/kg i.p.), the time course of pentobarbital levels in the serum and in the brain were not significantly different. The infusion of pentobarbital also did not induce hepatic drug-metabolizing enzymes. The depth of thiopental-induced hypothermia was decreased by i.c.v. pentobarbital 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 elevated. The increase in body temperature lasted for 8 days. Twenty-four hours after the infusion was discontinued, the pentobarbital-infused rats had a significantly shorter onset of t-butylbicyclophosphorothionate (TBPS)-induced convulsions. These studies show that i.c.v. infusion can be used to induce pentobarbital tolerance and dependence. This model has the advantage that issues related to induction of hepatic drug-metabolizing enzymes are eliminated, and it may be useful in the study of barbiturate addiction. ER -