HIGH-AFFINITY STEREOSPECIFIC BINDING OF CYCLODIENE INSECTICIDES AND GAMMA-HEXACHLOROCYCLOHEXANE TO GAMMA-AMINOBUTYRIC ACID RECEPTORS OF RAT-BRAIN

The GABA/benzodiazepine/picrotoxin receptor complex of rat brain was identified by the specific binding of 3 radiolabeled ligands in the same membrane preparation: [3H]flunitrazepam ([3H]Flu) for the benzodiazepine receptor site, [3H]muscimol for the GABA receptor site, and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) for the picrotoxinin site. Seven cyclodiene insecticides, .gamma.-BHC, .beta.-BHC and hexachlorobenzene had no significant effect on the specific binding of [3H]Flu or [3H]muscimol. But the cyclodienes and .gamma.-BHC were very potent in displacing [35S]TBPS binding with IC50 values ranging from 30 nM for endrin and endosulfan I to 500 nM for aldrin. Inhibition of [35S]TBPS binding by endrin was competitive. Binding was stereospecific since the more toxic stereoisomer of 3 pairs of compounds was more potent with the following IC50''s (in nM): endrin, 30; dieldrin, 100; endosulfan I, 30; endosulfan II, 60; .gamma.-BHC, 150; .beta.-BHC, > 10,000. Also the more toxic dieldrin epoxide and heptachlor epoxide had IC50''s of 100 and 70 nM, respectively, compared to 500 and 400 nM for the less toxic aldrin and heptachlor. respectively. The ionic channel of the GABA receptor in mammalian brain probably is a primary target for the toxic action of .gamma.-BHC and cyclodienes.