The proposed research serves the goal of placing the pharmacology, and the therapeutics, of the vestibular periphery on a firm, rational basis. This will be accomplished by identifying the transmitters involved in the efferent as well as the primary afferent synapses. Chemical transmission is a particularly drug-susceptible step in nervous function. Once the identities of these transmitters are known then drugs may be selected or designed which can potentiate or antagonize such transmitters, thus influencing vestibular function prophylactically or in disease states. The research involves a two-stage experimental procedure by which putative transmitters, their antagonists and mimetic agents may first be screened for activity in the vestibular periphery and secondly analyzed for site and mechanisms of action. The two stages, [1] screening and [2] analytical, will be served by three different in vitro preparations. The screening preparation will be the isolated whole labyrinth of the frog in which the spontaneous activities of any of the afferent nerves, auditory or vestibular may be monitored. This preparation is robust and reliable. The influence of putative transmitters and substances interacting with them on such spontaneous activity will be monitored. Substances exhibiting the ability to influence such activity in a dose-dependent, physiologically relevant manner will then be tested on two analytical preparations. The two analytical preparations will be the isolated semicircular canal of the frog arranged for recording single unit or population responses. These preparations permit mechanical evocation of hair-cell and nervous activity (population of single unit) and monitoring of both, and modification of either endolymph or perilymph. By these preparations, the site of action of an applied substance may be determined as well as possible mechanisms. The putative transmitters to be examined include: acetylcholine, the excitatory amino acids (glutamate and aspartate), purines (ATP and adenosine), GABA and substance P. Agents interacting with these transmitter candidates will also be tested.