The Benzodiazepine receptor and receptor tolerance produced by chronic treatment of Diazepam.

Abstract

A characterization of the benzodiazepine receptor in vivo was carried out utilizing the up-and-down method for a quantitative determination of the maximal seizure threshold to diazepam. Wistar-Imamichi male rats of 21 days of age were used. The drug concentration in the brain at the steady-state was measured with radiolabeled diazepam. A kinetic analysis for the dose-response relation obtained gave 2.2 .mu.M and 1.6 for the Kd and n, respectively, in the Langmuir adsorption isotherm. The results suggested the existence of a hitherto undiscovered endogenous ligand(s) suppressing the binding of benzodiazepine to the receptor, as compared with those in the in vitro binding-assay. A chronic pretreatment with diazepam once/day for 13 days (0.2 and 2 mg/kg, s.c.) produced receptor tolerance, but did not affect the amount of the seizure threshold unless the drug was acutely administered 10 min before the electric shock. Evidently, 2 distinct entities exist for both GABA and benzodiazepine recognition sites which are closely related to each other in their functioning.