REPEATED ADMINISTRATION OF DIAZEPAM REDUCES [H-3] RO 5-4864 BINDING IN CEREBRAL-CORTEX OF RATS

Binding of [H-3]Ro 5-4864 to mitochondrial membrane preparations of rat cerebral cortex was measured after repeated (5 days) IV administration of diazepam (10 mg/kg daily) and clonazepam (2.5 mg/kg daily). The B(max) value for [H-3]Ro 5-4864 was significantly reduced in rats treated with diazepam (-49%) but not in those treated with clonazepam. These findings suggest the involvement of peripheral-type binding sites in the development of rapid tolerance to the sedative effects of benzodiazepines. A downregulation of [H-3]Ro 5-4864 (-65%) was also observed after repeated administration of Ro 5-4864 (4 mg/kg daily), thus confirming that this compound behaves as an agonist at its own recognition sites.