Cyclodiene insecticides inhibit GABAA receptor-regulated chloride transport

The function of GABAA receptors in rat brain was assayed by GABA stimulation of 36Cl-influx into membrane microsacs. The evidence that the measured flux resulted from GABAA receptor activation was supported by the higher potency of muscimol than of GABA in inducing 36Cl-influx with Hill coefficients of 1.71 and 1.87, respectively, suggesting that two agonist molecules were binding to each receptor. Also, the GABA-induced 36Cl-influx was inhibited by the convulsants picrotoxinin and t-butylbicyclophosphorothionate (TBPS), and the competitive inhibitor (+)-bicuculline was more potent than (-)-bicuculline in inhibiting this 36Cl-influx. Furthermore, preincubation of the membranes with pentobarbital or diazepam increased the GABAA receptor's affinity for GABA as judged by the increased 36Cl-influx induced by the same GABA concentration without increasing maximal 36Cl-influx. The GABAA receptor was desensitized as shown by the dose-dependent reduction in GABA-induced 36Cl-influx that resulted from preincubation of the membranes with GABA. Seven cyclodienes inhibited the GABA-induced 36Cl-influx, with endosulfan I and endrin being more potent than their less toxic isomers endosulfan II and dieldrin, and the epoxides of heptachlor and aldrin (i.e., dieldrin) were more potent than their less toxic parent compounds. There was good correlation (r = 0.9) between inhibition of [35S]TBPS binding to rat brain membranes by these cyclodienes and their inhibition of GABA-induced 36Cl-influx.