The effect of ivermectin on gamma-aminobutyric acid (GABA)-induced Cl- currents was studied in embryonicse hippocampal cells in culture. When 0.1 microM ivermectin was applied to the perfusion medium, the responses to 2 microM GABA were enhanced to 273% within 60 s, and the GABA EC50 was reduced from 8.2 to 3.2 microM. 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 EC50 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 GABAA receptor and allosterically enhances the affinity of the GABA binding site. The more slowly occurring conformational changes in the ivermectin-GABAA receptor complex apparently accelerate the desensitization of the GABAA receptor, reducing the amplitude of maximal GABA-induced currents.