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. Whe n 0.1 mu M ivermectin was applied to the perfusion medium, the respons es to 2 mu M GABA were enhanced to 273% within 60 s, and the GABA EC(5 0) 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 tim e constants of GABA-activated membrane currents were shortened after i vermectin application. The final effect of ivermectin was irreversible . Modulation of the GABA responses by ivermectin did not interfere wit h the potentiation induced by diazepam and pentobarbital or with the s ensitivity to blockade by bicuculline, picrotoxin and Zn2+. These resu lts support the view that ivermectin binds to a novel site on the GABA (A) receptor and allosterically enhances the affinity of the GABA bind ing site. The more slowly occurring conformational changes in the iver mectin-GABA(A) receptor complex apparently accelerate the desensitizat ion of the GABA(A) receptor, reducing the amplitude of maximal GABA-in duced currents.