Effects of insecticides on GABA-induced chloride influx into rat brain microsacs

The actions of different insecticides known to affect binding of ligands to gamma-aminobutyric acid (GABA) receptors were studied on the function of GABAA receptors in rat brain as assayed by GABA-induced 36Cl- influx into membrane microsacs. This flux was inhibited by the competitive antagonist bicuculline and the noncompetitive antagonist t-butylbicyclophosphorothionate, and the GABA effect was potentiated by the tranquilizer flunitrazepam and the depressant pentobarbital, as expected for effects on a GABAA receptor. The GABA-induced 36Cl- flux was inhibited by several cyclodienes and gamma-hexachlorocyclohexane (gamma-BHC) with the following order of decreasing potency: endosulfan I greater than endrin greater than endosulfan II greater than dieldrin greater than heptachlor epoxide greater than gamma-BHC greater than heptachlor. The noninsecticidal beta-BHC had no effect, while the IC 50 values for gamma-BHC and endrin were 1 and 0.2 microM, respectively. The four pyrethroids tested also inhibited the GABA-induced 36Cl- flux with the following decreasing potencies: 1R,cis,alpha S-cypermethrin greater than 1R,trans, alpha S-cypermethrin greater than fluvalinate greater than allethrin. Avermectin B1a was the only insecticide tested that, in the absence of GABA, stimulated 36Cl- flux in a dose-dependent manner, and this flux was inhibited by bicuculline. The stereospecific inhibition of the GABA-induced 36Cl- influx by the cyclodienes and gamma-BHC supports previously published data on their binding to mammalian brain GABAA receptor and suggests that these insecticides inhibit this receptor's function. It is also suggested that type II pyrethroids are potent inhibitors of the same receptor. However, avermectin B1a appears to act as a partial agonist of GABAA receptors.