Activation of the GABA_A Receptor Ameliorates the Cochlear Excitotoxicity Caused by Kainic Acid in the Guinea Pig

Abstract

Excitotoxicity is a major neurotoxic mechanism in cochlear disorders, including cochlear ischemic injury and acoustic injury. Kainic acid (KA), an excitatory amino acid, can damage glutamatergic neurons. The application of KA to the round window membrane, an opening of the cochlear bony labyrinth to the middle ear, induces excitotoxicity of cochlear afferent dendrites and significantly decreases the amplitude of compound action potential of the cochlea (CAP), a cochlear potential generated by activation of the auditory nerve fibers. On the other hand, muscimol, a gamma-aminobutyric acid (GABA)_A receptor agonist, is neuroprotective in excitotoxicity in the central nervous system. Here we studied whether activation of GABA receptor decreased the excitotoxicity of the cochlea caused by KA. KA (10 mM) was applied to the round window membrane of guinea pigs for 30 minutes. Muscimol, bicuculline, a GABA_A receptor antagonist, or baclofen, a GABA_B receptor agonist, was given at the onset of KA application. The threshold shift of CAP was examined with chronically implanted electrodes. Application of KA significantly elevated the CAP threshold on day 1 and day 3 as compared with the pre-application level. Muscimol significantly decreased the KA-induced CAP threshold shifts. Furthermore, this protective effect of muscimol was inhibited by the application of bicuculline, a GABA_A receptor antagonist. However, baclofen, a GABA_B receptor agonist, did not affect the CAP threshold shifts caused by KA. These results suggest that activation of GABA_A receptor could prevent cochlear excitotoxicity. GABA_A rececptor activation may represent an effective treatment of cochlear ischemc injury and acoustic injury.