Induction of tolerance to and physical dependence on pentobarbital continuous intracerebroventricular administration.
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.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson.
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Kimura
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Miyaoka
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Saunders
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Baker
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Hume
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Yamamoto
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Ho
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D004361:Drug Tolerance; D015918:Infusion Pumps, Implantable; D007276:Injections, Intraventricular; D008297:Male; D008954:Models, Biological; D010634:Phenobarbital / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced; D019966:Substance-Related Disorders / Q000209:etiology*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; C037476:tert-butylbicyclophosphorothionate; D010634:Phenobarbital