Antagonism of ethanol and pentobarbital actions by benzodiazepine inverse agonists: neurochemical studies.
The benzodiazepine inverse agonist Ro 15-4513 has been shown to antagonize several behavioral effects of ethanol and to block the effects of ethanol on chloride flux across brain membranes. We used isolated mouse brain membranes to test whether Ro 15-4513 would reduce the effects of ethanol on membrane fluidity, voltage-dependent calcium channels, microsomal calcium release or binding of t-[35S]butylbicyclophosphorothionate. None of these actions of ethanol were altered by Ro 15-4513. The enhancement of gamma-aminobutyric acid (GABA)-activated chloride flux produced by ethanol or pentobarbital was antagonized partially by Ro 15-4513. Another inverse agonist, FG 7142, was more effective than Ro 15-4513 as an antagonist of ethanol actions on chloride flux. These results demonstrate that the ethanol antagonist action of Ro 15-4513 is specific for GABA-activated chloride flux and does not extend to other neurochemical actions of ethanol. The inverse agonist action (i.e., inhibition of GABA-activated chloride flux tested in the absence of ethanol) of Ro 15-4513 and FG 7142 was revealed by pretreatment of mice in vivo with ethanol. This raises the possibility that ethanol exposure increases the inverse agonist actions of Ro 15-4513 and related drugs and that these inverse agonist actions contribute to the ethanol antagonism observed in vivo and in vitro.
Harris
R A
RA
Veterans Administration Medical Center, Denver, Colorado.
Allan
A M
AM
Daniell
L C
LC
Nixon
C
C
D000818:Animals; D001386:Azides / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002118:Calcium / Q000378:metabolism; D002243:Carbolines / Q000494:pharmacology; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism; D000431:Ethanol / Q000037:antagonists & inhibitors*; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D010424:Pentobarbital / Q000037:antagonists & inhibitors*; D011963:Receptors, GABA-A / Q000187:drug effects*
D001386:Azides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002243:Carbolines; D018118:Chloride Channels; D002712:Chlorides; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; C035874:FG 7142; C037476:tert-butylbicyclophosphorothionate; C042957:Ro 15-4513; D010424:Pentobarbital; D002118:Calcium