Nonlinear relationship between benzodiazepine receptor occupancy and glucose metabolic response in the conscious mouse brain in vivo.

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%).