Drug manipulation of noise-induced hearing loss

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DESCRIPTION (provided by applicant): The long-term objective of this research is to develop drugs that will decrease the effects of intense sound on the cochlea. Recent results from our laboratory have shown that PPADS, an ATP antagonist, decreases the effect of intense sound on the cochlea as monitored with distortion product otoacoustic emissions (DPOAEs). Our working hypothesis is that PPADS is blocking the effects of endogenous ATP acting on receptors on the perilymph surface of Deiters' cells. Exogenously applied ATP depolarizes Deiters' cells and increases their intracellular free calcium levels. Deiters' cells are innervated by what appears to be branches of type II afferents to the outer hair cells (OHCs). This suggests that the source of the ATP acting on ATP receptors on the Deiters' cells may be the terminals of these nerve fibers. Anatomically, Deiters' cells are attached to the base and apex of OHCs, to the basilar membrane, and reticular lamina. Thus Deiters' cells may play a significant role in the transduction process carried out by the OHCs and their stereocilia. Deiters' cells may do this by altering their own stiffness. The hypothesis to be tested is that ATP, proposed as a neurotransmitter in the cochlea, reacts with receptors on the Deiters' cells to enhance the deleterious effects of intense sound on the cochlea. This hypothesis will be tested by experiments that: (1) determine if endogenous ATP enhances the deleterious effects of intense sound by testing ATP agonists and antagonists during intense sound exposure; (2) determine if the mechanism of action of ATP involves a movement of Deiters' cell or a stiffness change; and (3) determine if the receptor mechanism on Deiters' cells involves the metabotropic P2Y type of receptor.