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

1994; American Society for Pharmacology and Experimental Therapeutics; Volume: 268; Issue: 2 Linguagem: Inglês

10.1016/s0022-3565(25)38992-5

1521-0103

Yuming Wu, Howard C. Rosenberg, Ted H. Chiu, Vicki Ramsey-Williams,

Memory and Neural Mechanisms

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.