Systematic assessment of tolerance to pentobarbital by pellet implantation

Rapid tolerance development to pentobarbital by pentobarbital pellet implantation was evidenced by a decrease in sleeping time after challenge with different doses of sodium pentobarbital ranging from 37.5 to 100 mg/kg i.p. or a fixed dose of 75 mg/kg i.p. of the drug. The sleeping time produced by sodium pentobarbital decreased by 50% after 1 day. After 2 or 3 days of implantation, the sleeping time was generally further decreased to 15 to 20% of the placebo control group. Tolerance to pentobarbital was still evident 72 hours after pellet removal. The tolerance development to pentobarbital by pentobarbital pellet implantation also was demonstrated by other pentobarbital-induced responses such as hypothermia and lethality. In mice implanted with a 75-mg pentobarbital pellet for 3 days, the degree and duration of pentobarbital-induced hypothermia by intraperitoneal or intracerebral administration of the drug was attenuated. The chronic administration of pentobarbital by three days of pellet implantation reduced the effect of sodium pentobarbital on lethality as evidenced by an increase in the LD50 of sodium pentobarbital after intraperitoneal or intracerebral administration of the drug.