Interaction of the neurotoxic pesticides ivermectin and lindane with the enteric GABAA receptor-ionophore complex in the guinea-pig

In isolated segments of guinea-pig small intestine, γ-aminobutyric acid (GABA) (3-300 μM), the GABA_A receptor agonist 3-aminopropane sulphonic acid (3-APS) (3-300 μM) and ivermectin (1-300 μM) caused concentration-dependent nerve-mediated cholinergic contractions sensitive to tetrodotoxin (1 μM) and hyoscine (1 μM). The EC₅₀ values were 30.2±4.3, 24.6±3.1 and 4.8±0.6 μM, respectively. Picrotoxinin (10 μM), an allosteric blocker of the Cl^- channel associated with GABA_A receptors, non-competitively antagonized the contractile response caused by each agonist. Like picrotoxinin, lindane (10, 30 μM) caused a dose-related shift to the right of the concentration-response curve to GABA, 3-APS and ivermectin with depression of the maximum response. SR 95531 (3 μM), a competitive antagonist of GABA_A receptors, caused a parallel dextral shift of the concentration-response curve to ivermectin with an apparent single point pA₂ value of 6.5. Our results suggest that ivermectin and lindane, two neurotoxic pesticides interfering with central GABAergic transmission, exert agonist and non-competive antagonist properties at the enteric GABA_A receptor-ionophore complex. This peripheral complex can thus be considered as an additional target for the action of both these compounds.