Although chemicals that interact with receptors for neurotransmitters can be powerful tools for investigation or for therapy, few such chemicals are available for use in the auditory and vestibular systems. To a great extent, this lack of chemical tools stems from the lack of knowledge about the chemistry of neurotransmission in these hair-cell sensory organs. If the transmitter released by hair cells could be identified, drugs could be synthesized to mimic or to block its actions. Such drugs would be helpful in basic studies of auditory and vestibular function, and could prove useful in alleviating some of the symptoms of disorders of hearing and equilibration, such as motion sickness, Meniere's disease, and peripheral tinnitus. The goal of this project is to identify the hair-cell neurotransmitter(s). The strategy is to examine extracts of hair- cell tissue for substances that can alter the firing rate of afferent nerves innervating a hair-cell sensory organ. Any active substance found will be isolated and identified. Its specific role in inner ear function will be determined. This strategy can be successful even if the hair-cell transmitter is not one of the known neurotransmitters, and even if many active substances are present in hair cells. Extracts of the inner ears of fish can excite afferent fibers innervating hair cells in the lateral line organ of the African clawed frog (Xenopus laevis). These extracts have at least two excitatory components separable by molecular weight. The first specific aim is to purify the low-molecular-weight excitatory component. If possible, it will be identified by comparison of its properties with those of known substances. If not, purification techniques will be devised to obtain enough material for its chemical identification. The second specific aim is to purify the high-molecular-weight excitatory component and to determine if it is accounted for by calcitonin-gene-related peptide (CGRP), a neuroactive peptide present in inner ear tissue and shown in this project to activate afferent neurons. The third specific aim is to perform physiological analysis of the site and mechanism of action of chemicals identified as neurotransmitter candidates by this approach. These experiments will based on analysis of synaptic potentials in goldfish auditory nerve fibers and membrane potentials of cultured, dissociated goldfish VIIIth-nerve ganglion cells.
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