The selective AMPA receptor antagonist GYKI 53784 blocks action potential generation and excitotoxicity in the guinea pig cochlea

The role of AMPA receptors in cochlear synaptic transmission and excitotoxicity was investigated by comparing the actions of a selective AMPA antagonist GYKI 53784 (LY303070) with additional AMPA/kainate antagonists, GYKI 52466 and DNQX, and the NMDA antagonist, D-APS, in several electrophysiological, neurotoxicological and histochemical tests. GYKI 53784 had the same potency as DNQX and was 10 times more potent than CYKI 52466 in reducing auditory nerve activity. The NMDA antagonist D-APS had no effect on auditory nerve activity. When single-fiber activity was blocked with GYKI 53784, the effects of AMPA or kainate were also antagonized. GYKI 53784 completely blocked excitotoxicity (i.e. destruction of the afferent nerve endings) induced by AMPA and kainate. The histochemical detection of Co2+ uptake was used to study Ca2+ influx within the primary auditory nerve cells. Application of AMPA induced no significant Co2+ uptake into the cells, suggesting that these receptors normally have a very low permeability to Ca2+. Application of kainate induced significant Co2+ uptake that was blocked by the AMPA receptor antagonist GYKI 53784 suggesting that kainate stimulated Ca2+ entry through AMPA receptor channels. Results suggest that AMPA-preferring receptors are functionally located at the sensory cell-afferent synapse whereas NMDA and kainate receptors are not. (C) 2000 Elsevier Science Ltd. All rights reserved.