Effects of adenosine 5'-triphosphate and related agonists on cochlear function

Several lines of evidence implicate a neurotransmitter/modulator role for ATP in the cochlea. Most of the work supporting such a notion has been accomplished using in vitro preparations of sensory hair cells or other cochlear tissues. Little is known regarding the functional consequences of ATP receptor activation in vivo. In the present experiments, we tested ATP and related agonist analogs for their effects on sound-evoked responses of the cochlea (cochlear microphonic, CM; summating potential, SP; distortion product otoacoustic emissions, DPOAE) and auditory nerve (compound action potential, CAP) in vivo and on outer hair cell (OHC) currents and cell length in vitro. In vivo, local application of these compounds was associated with concentration- and intensity-dependent response alterations. The slowly-hydrolyzable P2y agonist, ATP-gamma-S, was clearly of greatest in vivo potency: At low to moderate stimulus intensities, micromolar concentrations of this drug reduced all responses, in particular CAP and DPOAEs, which fell to the level of the noise floor. At high intensities, response suppression was smaller and SP was increased. In vivo effects of ATP, ATP-alpha-S and 2-Me-S-ATP were qualitatively similar to, but smaller in magnitude and requiring higher concentrations than those observed for ATP-gamma-S. Adenosine was without significant effect on responses of the cochlea and auditory nerve. In vitro, effects of ATP-gamma-S and ATP were similar: both induced inward currents in OHCs held at -60 mV without producing observable (> 0.3 micron) changes in OHC length. Results suggest that endogenous ATP influences cochlear function through receptors at several sites in the cochlea. Results suggest further that these response alterations are mediated, at least in part, by receptors of the P2y subtype.