Quantitative relationship between in vivo receptor occupancy of psychotropic and the change of glucose utilization in brain

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To evaluate the relationship between the pharmacological effect of benzodiazepine (BZP) and BZP receptor binding in the conscious mouse brain, a response of the glucose utilization (GU) to clonazepam (CNZ) or zolpidem was measured as an index for the pharmacological effect. GU was measured by the simultaneous use of [14C]2-deoxyglucose (2DG), the glucose analogue which can be phosphorylated in the brain, and [3H]3-0-methylglucose (3MG), the nonmetabolizable glucose analogue. The distribution volume of unphosphorylated 2DG in the brain was not significantly different from that of 3MG (VM), indicating that the phosphorylation rate of 2DG can be estimated by subtracting VM from apparent volume of distribution of 2DG. By this double tracer technique, it is possible to determine GU within 10 min after administration of both tracers. Pharmacological and pathophysiological changes of the isotope correction factor (lumped constant) can also be estimated by this technique.In the cerebral cortex … More , GU decreased to 70-80 % at 60 min after i.v. administration of CNZ (0.005-1.0 mg/kg), and this effect was completely diminished by the administration of a benzodiazepine 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 bad very little additional effect. In vivo BZP receptor occupancy, measured using [3H]Ro-15-1788, 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 mg/kg 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 exerts the maximum glucose metabolic change at a low fractional receptor occupancy (30-40%). In zolpidem similar results were also obtained. By using positron emission tomography, these techniques can be applied to living human brain, which makes it possible to determine the optimal doses of BZP in the effective therapeutic drug monitoring. Less