Regional changes in [3H]zolpidem binding to brain benzodiazepine receptors in flurazepam tolerant rat: comparison with changes in [3H]flunitrazepam binding.
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.
Wu
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Y
Department of Pharmacology and Therapeutics, Medical College of Ohio, Toledo.
Rosenberg
H C
HC
Chiu
T H
TH
Ramsey-Williams
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V
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003975:Diazepam / Q000494:pharmacology; D004361:Drug Tolerance; D005445:Flunitrazepam / Q000378:metabolism*; D005479:Flurazepam / Q000494:pharmacology*; D008297:Male; D011725:Pyridines / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014316:Tritium; D000077334:Zolpidem
D011725:Pyridines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam; D000077334:Zolpidem; D005479:Flurazepam; D003975:Diazepam