Are the toxicities of pentobarbital and ethanol mediated by the GABA-benzodiazepine receptor-chloride ionophore complex?
Both barbiturates and ethanol have been reported to interact with the GABA-benzodiazepine receptor-chloride ionophore 'supramolecular complex'. These observations raise the possibility that some of the pharmacologic actions of barbiturates and ethanol may be mediated through this complex. In this study we have administered a series of drugs which bind to various components of the complex in an attempt to antagonize the lethality of sodium pentobarbital, and ethanol-induced loss of righting reflex in mice. It was found that isopropylbicyclophosphate (IPPO), a cage convulsant which binds at or near the chloride ionophore, greatly reduces the overall mortality (and increases latency to death) of animals pretreated with a lethal dose of pentobarbital. Picrotoxin also decreases pentobarbital lethality, but only at doses which were usually lethal when given alone. Picrotoxin shortened, rather than increased, latency to death. Strychnine did not prevent pentobarbital lethality, suggesting that the IPPO effect is not shared by convulsants in general. IPPO did not prevent ketamine-induced deaths, which supports the notion that the protective actions of IPPO are specific for depressant drugs which act at the chloride ionophore. IPPO also significantly reduced the duration of loss of righting reflex induced by ethanol. These observations suggest that the use of compounds which have a high affinity for the chloride ionophore in vitro might be fruitful in developing a clinical treatment for barbiturate or ethanol toxicity.
Mendelson
W B
WB
Martin
J V
JV
Wagner
R
R
Roseberry
C
C
Skolnick
P
P
Weissman
B A
BA
Squires
R
R
D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D000431:Ethanol / Q000633:toxicity*; D007476:Ionophores / Q000494:pharmacology*; D007649:Ketamine / Q000633:toxicity; D008297:Male; D051379:Mice; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010424:Pentobarbital / Q000633:toxicity*; D010852:Picrotoxin / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D012018:Reflex / Q000187:drug effects; D013331:Strychnine / Q000494:pharmacology
D002712:Chlorides; D000431:Ethanol; D007476:Ionophores; D007649:Ketamine; D009943:Organophosphorus Compounds; D010424:Pentobarbital; D010852:Picrotoxin; D011720:Pyrazoles; D011963:Receptors, GABA-A; D013331:Strychnine; C031012:dihydropicrotoxinin receptor; C008207:4-isopropylbicyclophosphate; C033830:2-phenylpyrazolo(4,3-c)quinolin-3(5H)-one