Ligand-dependent effects of ethanol and diethylether at brain benzodiazepine receptors.
The GABAA receptor chloride channel complex interacts with various categories of sedatives, including the benzodiazepines, and possibly ethanol and volatile general anesthetics. Thus, specific binding of tritiated derivatives of a benzodiazepine antagonist, flumazenil, and an agonist, flunitrazepam, to rat brain membrane fragments was monitored at equilibrium in the presence and absence of anesthetizing concentrations of ethanol and diethylether. Ethanol produced a concentration-dependent inhibition of [3H]flumazenil binding, which was not reversed by the GABAA receptor competitive antagonist bicuculline, but had no effect on [3H]flunitrazepam binding. Both ethanol and diethylether decreased the affinity of the benzodiazepine site for [3H]flumazenil. These data indicate that ethanol and diethylether have GABA-independent effects at the benzodiazepine sites of the GABAA receptor. These findings are inconsistent with a two-state functional model of the benzodiazepine site and, instead, support a model containing a specific, antagonist-favored conformation.
Quinlan
J J
JJ
Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh, PA 15213.
Firestone
L L
LL
D000818:Animals; D000431:Ethanol / Q000494:pharmacology*; D004986:Ether / Q000494:pharmacology*; D005442:Flumazenil / Q000378:metabolism; D005445:Flunitrazepam / Q000378:metabolism; D008024:Ligands; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
D008024:Ligands; D011963:Receptors, GABA-A; D004986:Ether; D000431:Ethanol; D005442:Flumazenil; D005445:Flunitrazepam