Effects of quinine on the excitability and voltage-dependent currents of isolated spiral ganglion neurons in culture.

Abstract

This work examined how quinine, a drug that induces both hearing loss and tinnitus, interfered with the excitability of spiral ganglion (SG) neurons in cultures. The membrane potential changes and the modification of the action-potential waveform induced by quinine were studied in SG neurons under current clamp. The effects of the drug on voltage-dependent currents in SG neurons were also investigated by the voltage-clamp method. Quinine did not appreciably affect either resting membrane potentials or input resistance at rest. However, action potentials fired by SG neurons were significantly broadened by the presence of quinine. With higher concentrations of quinine (>20 microM), the amplitude of action potentials was also reduced. Voltage-clamp results demonstrated that quinine primarily blocked the whole cell potassium currents (IK) in a voltage-dependent manner. Up to 100 microM of quinine did not appreciably block IK evoked by a test pulse to -35 mV. In contrast, IK was significantly reduced with more positive test pulses, e.g., the concentration needed to obtain 50% inhibition (IC50) was 8 microM for a test pulse to 65 mV. At higher concentrations (>20 microM), quinine also reduced the size of sodium currents (INa) in a use-dependent manner, while leaving calcium currents (ICa) relatively unaffected. Compared with the potency of quinine's effects on other targets in the inner ear, the relatively low IC50 and the voltage-dependent nature of quinine inhibition on IK suggested that its modulation of the waveform and threshold of action potentials of SG neurons probably was primarily responsible for its ototoxic effects. From the point of view of how neural signaling process is affected by the drug, quinine-induced tinnitus may be explained by its broadening of action potentials while the drug's inhibition on INa may result in hearing loss by making the conversion from excitatory postsynaptic potentials to the generation of action potentials more difficult.