Effects of Ototoxins on Quinuclidinyl Benzylate Binding in the Rat Cochlea

Ototoxins inhibit the muscarinic receptor-activated inositol phosphate synthesis in the rat cochlea. In order to study this inhibitory mechanism, we investigated the effects of the ototoxins ethacrynate, cisplatin, HgCl2 and neomycin on [3H]quinuclidinyl benzylate binding to muscarinic receptors in adult and 12-day-old rat cochleas. The results are similar whatever the age: at concentrations that inhibit the inositol phosphate synthesis, ethacrynate is without effect. Neomycin only reduces [3H]quinuclidinyl benzylate binding at concentrations in the millimolar range. Cisplatin and HgCl2 block the binding in a dose-dependent way. These results suggest that the block of the transduction system by cisplatin and HgCl2 is due to direct interactions with muscarinic binding sites. Moreover, considering these data together with previous results, ethacrynate and neomycin may affect the phosphoinositide signalling pathway at targets including phosphoinositides and G proteins.