Regional changes in [3H]zolpidem binding to brain benzodiazepine receptors in flurazepam tolerant rat: comparison with changes in [3H]flunitrazepam binding

Y Wu, HC Rosenberg, TH Chiu and V Ramsey-Williams

Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo.

Regional downregulation of brain benzodiazepine (BZ) receptors was studied in rats treated with flurazepam or diazepam protocols known to produce anticonvulsant tolerance. Zolpidem, a selective BZ1 receptor agonist, was used to detect BZ1 receptors; flunitrazepam, a nonselective BZ receptor agonist, was used to detect the total BZ receptor population. Rats were treated 4 weeks with flurazepam, then sacrificed immediately or 48 hr later. After flurazepam treatment, the maximal binding capacity of [3H]zolpidem binding decreased 22% in the cerebral cortex, 32% in the cerebellum and 25% in the hippocampus. The Kd increased in the cerebellum. The maximal binding capacity of [3H]flunitrazepam binding decreased by 13% in the cerebral cortex and 14% in the hippocampus, but did not change in the cerebellum. The Kd increased in the hippocampus. At 48 hr after flurazepam treatment, there was no significant difference in [3H]zolpidem binding between treated and control rats. In rats treated 3 weeks with diazepam released from s.c. reservoirs, there was no change in [3H]zolpidem binding. The data suggest that chronic flurazepam treatment causes downregulation primarily involving BZ1 receptors. The differing effects on [3H]-zolpidem and [3H]flunitrazepam binding, especially in the cerebellum in which more than 90% of the receptors are the BZ1 subtype, may indicate a shift in BZ receptor subtypes in flurazepam-tolerant rats, suggesting a change in the subunit composition or conformation of gamma-aminobutyric acidA/BZ receptors.

Volume 268, Issue 2, pp. 675-682, 02/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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