Effects of AUT00063, a Kv3.1 channel modulator, on noise-induced hyperactivity in the dorsal cochlear nucleus

The purpose of this study was to test whether a Kv3 potassium channel modulator, AUT00063, has therapeutic potential for reversing noise-induced increases in spontaneous neural activity, a state that is widely believed to underlie noise-induced tinnitus. Recordings were conducted in noise exposed and control hamsters from dorsal cochlear nucleus (DCN) fusiform cells before and following intraperitoneal administration of AUT00063 (30 mg/kg). Fusiform cell spontaneous activity was increased in sound-exposed animals, approximating levels that were nearly 50% above those of controls. Administration of AUT00063 resulted in a powerful suppression of this hyperactivity. The first signs of this suppression began 13 min after AUT00063 administration, but activity continued to decline gradually until reaching a floor level which was approximately 60% of pre-drug baseline by 25 min after drug treatment. A similar suppressive effect of AUT00063 was observed in control animals, with onset of suppression first apparent at 13 min post-treatment, but continuing to decline toward a floor level that was 54% of pre-drug baseline and was reached 28 min after drug treatment. In contrast, no suppression of spontaneous activity was observed in animals given similar injections of vehicle (control) solution. The suppressive effect of AUT00063 was achieved without significantly altering heart rate and with minimal effects on response thresholds, supporting the interpretation that the reductions of hyperactivity were not a secondary consequence of a more general physiological suppression of the brain or auditory system. These findings suggest that Kv3 channel modulation may be an effective approach to suppressing spontaneous activity in the auditory system and may provide a future avenue for treatment of tinnitus resulting from exposure to intense sound.