RT Journal Article
SR Electronic
T1 Nonlinear relationship between benzodiazepine receptor occupancy and glucose metabolic response in the conscious mouse brain in vivo.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 362
OP 367
VO 251
IS 1
A1 Ishizuka, H
A1 Sawada, Y
A1 Ito, K
A1 Sugiyama, Y
A1 Suzuki, H
A1 Iga, T
A1 Hanano, M
YR 1989
UL http://jpet.aspetjournals.org/content/251/1/362.abstract
AB 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%).