Abstract

The effect of muscimol, a GABAA receptor agonist, on the basic metabolic activity was investigated in the mouse brain and was correlated with its receptor occupancy. For the quantitative evaluation of the functional activity of the mouse brain, the cerebral glucose utilization was measured by the double tracer technique, using [14C] 2-deoxyglucose and [3H]3-O-methylglucose. The dose-dependent reduction in the cerebral glucose utilization was observed after intravenous administration of various doses of muscimol (0.3-1.5 mg/kg). On the other hand, the GABAA receptor occupancy of muscimol was determined by using the values of the unbound drug concentration in the brain tissue and the receptor dissociation constant based on the in vitro binding experiments using the dissociated brain cells. The tissue unbound concentration of muscimol was calculated by multiplying the total concentration in the brain after administration of muscimol and the tissue unbound fraction, which was measured by the equilibrium dialysis method using brain tissue homogenate. A linear relationship was observed between the GABAA receptor occupancy of muscimol and the decrease in the cerebral glucose utilization. This finding indicates that the simple receptor occupancy theory holds for this receptor-ligand system, and there is a large difference in the effect on glucose metabolic response between GABAA receptor-agonist interaction and benzodiazepine receptor-agonist interaction.