INTERACTION OF THE NEUROTOXIC PESTICIDES IVERMECTIN AND LINDANE WITH THE ENTERIC GABA(A)-RECEPTOR-IONOPHORE COMPLEX IN THE GUINEA-PIG

In isolated segments of guinea-pig small intestine, gamma-aminobutyric acid (GABA) (3-300 muM), the GABA(A) receptor agonist 3-aminopropane sulphonic acid (3-APS) (3-300 muM) and ivermectin (1-300 muM) caused concentration-dependent nerve-mediated cholinergic contractions sensitive to tetrodotoxin (1 muM) and hyoscine (1 muM). The EC50 values were 30.2 +/- 4.3, 24.6 +/- 3.1 and 4.8 +/- 0.6 muM, respectively. Picrotoxinin (10 muM), 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 muM) 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 muM), 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.