Polychlorinated convulsant insecticides potentiate the protective effect of NaCl against heat inactivation of [3H]flunitrazepam binding sites.
Six polychlorinated convulsant insecticides that potently inhibit t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to rat brain membranes also potentiate the protective effect of NaCl (200 mM) against heat inactivation of [3H]flunitrazepam binding sites on the same membranes. Similar effects were obtained with all "cage" convulsants tested. The rank order of potencies as heat protection potentiators was similar to the rank order of potencies as inhibitors of [35S]TBPS binding (alpha-endosulfan greater than endrin greater than dieldrin greater than toxaphene greater than lindane). alpha-Endosulfan and endrin are more potent in both respects than any previously reported picrotoxin-like (cage) convulsant, but are much less toxic to mammals. The greatly reduced toxicities of alpha-endosulfan and endrin in mammals may reflect partial gamma-aminobutyric acid (GABA)-neutral properties of these compounds. Time courses of heat inactivation of [3H]flunitrazepam binding sites in the presence of 200 mM NaCl plus saturating concentrations of endrin or picrotoxin revealed monophasic components constituting about 88% of the binding sites, suggesting that virtually all [3H]flunitrazepam binding sites are coupled to picrotoxin binding sites in the GABA/benzodiazepine/picrotoxin receptor complex. Protection against heat inactivation constitutes a useful tool for characterizing the various allosterically linked binding sites in neurotransmitter receptor complexes.
Squires
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Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
Saederup
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D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002462:Cell Membrane / Q000378:metabolism; D002675:Child, Preschool; D004026:Dieldrin / Q000494:pharmacology; D004357:Drug Synergism; D004726:Endosulfan / Q000494:pharmacology; D004732:Endrin / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism*; D001556:Hexachlorocyclohexane / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology*; D014112:Toxaphene / Q000494:pharmacology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007306:Insecticides; D011963:Receptors, GABA-A; D012965:Sodium Chloride; D001556:Hexachlorocyclohexane; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D014112:Toxaphene; D004026:Dieldrin; D004732:Endrin; D004726:Endosulfan