Binding characteristics of 3H-flunitrazepam and CL-218,872 in cerebellum and cortex of C57B1 mice made tolerant to and dependent on phenobarbital or ethanol.

The influence of chronic phenobarbital (PB) or chronic ethanol administration on binding characteristics of 3H-flunitrazepam (3H-FLU) in cerebellum and cortex of C57Bl mice was examined. Chronic PB treatment for six days decreased the number of binding sites (Bmax) for 3H-FLU, whereas no change in the affinity (KD) was found. Further kinetic analysis revealed that the overall decrease in Bmax was due to a reduced number of high affinity (Type 1) benzodiazepine (BDZ) binding sites in the cerebellum, but to a decreased number of low affinity (Type 2) BDZ binding sites in the cortex. Furthermore, a marked reduction in the pentobarbital-produced enhancement of 3H-FLU binding was observed in the cerebellum of the PB-treated animals. Following chronic ethanol administration for seven days, no change in the Bmax or in the KD could be demonstrated. However, in chronically ethanol-treated mice, the pentobarbital-induced stimulation of 3H-FLU binding was reduced in the cerebellum of mice 24 hours after discontinuation of the ethanol treatment. The significance of the present findings for the development of tolerance to and dependence on barbiturates and ethanol is discussed.