EFFECT OF IVERMECTIN ON GAMMA-AMINOBUTYRIC ACID-INDUCED CHLORIDE CURRENTS IN MOUSE HIPPOCAMPAL EMBRYONIC NEURONS

The effect of ivermectin on gamma-aminobutyric acid (GABA)-induced Cl- currents was studied in embryonicse hippocampal cells in culture. When 0.1 mu M ivermectin was applied to the perfusion medium, the responses to 2 mu M GABA were enhanced to 273% within 60 s, and the GABA EC(50) was reduced from 8.2 to 3.2 mu M. Half-maximal potentiation of GABA responses was found with 17.8 nM ivermectin. The potentiating effect of ivermectin diminished to 146% within 10 min but the GABA EC(50) did not change any further. At the same time, the maximal GABA-induced Cl- current decreased to 64%. Both the fast and slow desensitization time constants of GABA-activated membrane currents were shortened after ivermectin application. The final effect of ivermectin was irreversible. Modulation of the GABA responses by ivermectin did not interfere with the potentiation induced by diazepam and pentobarbital or with the sensitivity to blockade by bicuculline, picrotoxin and Zn2+. These results support the view that ivermectin binds to a novel site on the GABA(A) receptor and allosterically enhances the affinity of the GABA binding site. The more slowly occurring conformational changes in the ivermectin-GABA(A) receptor complex apparently accelerate the desensitization of the GABA(A) receptor, reducing the amplitude of maximal GABA-induced currents.