Received for publication February 25, 2008.
Revised June 4, 2008.
Accepted for publication June 4, 2008.

Midazolam Reverses Salicylate Induced Changes in BDNF and Arg3.1 Expression: Implications for Tinnitus Perception and Auditory Plasticity

Abstract

Tinnitus is a phantom auditory perception, which can be induced via application of concentrated sodium salicylate, and is known to be associated with hearing loss and altered neuronal excitability in peripheral and central auditory neurons. The molecular features of this excitability has, however, been poorly characterized to date. Brain derived neurotrophic factor (BDNF), the activity-dependent cytoskeletal protein (Arg3.1, also known as Arc), and c-Fos are known to be affected by changes in excitability and plasticity. Using RT-PCR, in situ hybridization and immunohistochemistry, the expression of these genes was monitored in the rat auditory system following local (cochlear) and systemic application of salicylate. Induction of tinnitus and hearing loss was verified in a behavioural model. Regardless of the mode of salicylate application, a common pattern became evident: (1) BDNF mRNA expression was increased in the spiral ganglion neurons of the cochlea and (2) Arg3.1 expression was significantly reduced in the auditory cortex (AC). Local application of the GABA_A receptor modulator midazolam resulted in the reversal not only of salicylate induced changes in cochlear BDNF expression, but also in cortical Arg3.1 expression, indicating that the tinnitus associated changes in cochlear BDNF expression trigger the decline of cortical Arg3.1 expression. Furthermore, local midazolam application reduced tinnitus perception in the animal model. These findings support Arg3.1 and BDNF as markers for activity changes in the auditory system and suggest a role of GABA-ergic inhibition of cochlear neurons in the modulation of Arg3.1 plasticity changes in the auditory cortex and tinnitus perception.

Key words: Immunocytochemistry, In situ hybridization, Synaptic plasticity