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The Journal of Neuroscience, May 1, 2003, 23(9):3944

Salicylate Induces Tinnitus through Activation of Cochlear NMDA Receptors

Matthieu J. Guitton¹, Jean Caston², Jérôme Ruel¹, Randolph M. Johnson³, Rémy Pujol¹, and Jean-Luc Puel¹

¹ Institut National de la Santé et de la Recherche Médicale UR-254, Laboratoire de Neurobiologie de l'Audition-Plasticité Synaptique, Faculté de Médecine, Université de Montpellier 1, 34090 Montpellier, France, ²  Unité Propre de Recherche et de l'Enseignement Supérieur 1780, Laboratoire de Neurobiologie de l'Apprentissage, Université de Rouen, 76821 Mont-Saint-Aignan, France, and ³ DURECT Corporation, Cupertino, California 95014

Salicylate, the active component of aspirin, is known to induce tinnitus. However, the site and the mechanism of generation of tinnitus induced by salicylate remains unclear. Here, we developed a behavioral procedure to measure tinnitus in rats. The behavioral model was based on an active avoidance paradigm in which rats had to display a motor task (i.e., to jump on a climbing pole when hearing a sound). Giving salicylate led to a decrease in the percentage of correct responses (score) and a drastic increase in the number of false positive responses (i.e., animals execute the motor task during a silent period). Presentation of the sound at a constant perceptive level prevents decrease of the score, leading to the proposal that score is related to hearing performance. In contrast, the increase of false positive responses remained unchanged. In fact, animals behaved as if they hear a sound, indicating that they are experiencing tinnitus. Mefenamate in place of salicylate also increased the number of false positive responses, suggesting that salicylate-induced tinnitus is related to an inhibition of cyclooxygenase. One physiological basis of salicylate ototoxicity is likely to originate from altered arachidonic acid metabolism. Because arachidonic acid potentiates NMDA receptor currents, we tested the involvement of cochlear NMDA receptors in the occurrence of tinnitus. Application of NMDA antagonists into the perilymphatic fluids of the cochlea blocked the increase in pole-jumping behavior induced by salicylate, suggesting that salicylate induces tinnitus through activation of cochlear NMDA receptors.

Key words: tinnitus; NMDA receptor; local therapy; cyclooxygenase pathway; behavioral model; salicylate

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2393944-09$05.00/0

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