title: Nonlinear relationship between benzodiazepine receptor occupancy and glucose metabolic response in the conscious mouse brain in vivo.
abstract: To evaluate the relationship between the pharmacological effect of benzodiazepine (BZP) and BZP receptor (BZP-R) binding in the conscious mouse brain, a response of the local cerebral metabolic rate of glucose utilization (GU) to clonazepam (CNZ) was measured as an index for the pharmacological effect. Two glucose analogs (3-O-[3H]methylglucose and 2-[14C]deoxyglucose) method, originally presented by A. Gjedde was used for determination of GU. In the cerebral cortex, GU decreased to 70 to 80% at 60 min after i.v. administration of CNZ (0.005-1.0 mg/kg), but CNZ did not change the lumped constant, and this effect was diminished completely by the administration of a BZP antagonist, Ro-15-1788 (5 mg/kg). The maximum effect of CNZ on GU (about 30% decrease) was found at 0.1 mg/kg of CNZ, but increasing the dose to 1 mg/kg had very little additional effect. In vivo BZP-R occupancy was measured using [3H]-Ro-15-1788. Receptor occupancy increased from less than 10% at a dose of 0.005 mg/kg up to essentially 100% at doses of 1 mg/kg or greater. ID50 in dose-response curve of the receptor occupancy for CNZ and ED50 in that of decrease in GU were 0.3 and 0.007 mg/kg, respectively . A nonlinear and hyperbolic relationship was observed between the receptor occupancy and the response for the glucose metabolic rate, indicating that BZP exert the maximum glucose metabolic change at a low fractional receptor occupancy (30-40%).
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ishizuka
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: Y
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: T
authors.initials: T
authors.lastname: Iga
authors.forename: M
authors.initials: M
authors.lastname: Hanano
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002998:Clonazepam / Q000378:metabolism / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D002998:Clonazepam; D005947:Glucose