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

Abstract

The actions of different insecticides known to affect binding of ligands to y‐amino‐butyric acid (GABA) receptors were studied on the function of GABA_A 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 GABA_A receptor. The GABA‐induced ³⁶Cl^‐ flux was inhibited by several cyclo‐dienes and y‐hexachlorocyclohexane (γ‐BHC) with the following order of decreasing potency: endosu/fan I > endrin > endosulfan II > dieldrin > heptachlor epoxide > y‐BHC > heptachlor. The noninsecticidal β‐BHC had no effect, while the IC 50 values for y‐BHC and endrin were 7 and 0.2 μM, respectively. The four pyrethroids tested also inhibited the GABA‐induced ³⁶Cl^‐ flux with the following decreasing potencies: 1R,cis,αS‐cypermethrin > 1R, trans,αS‐cypermethrin > fluvalinate > allethrin. Aver‐mectin B_1a 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 γ‐BHC supports previously published data on their binding to mammalian brain ABA_A 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 B_1a appears to act as a partial agonist of CABA_A receptors.