Salicylate-induced Dynamic Changes Of Glutamate And GABA Receptors In The Mechanism Of Tinnitus

Objective:To investigate the dynamic changes of glutamate and?-aminobutyric acid(GABA) receptors and neurotransmitters in an animal model of salicylate-induced tinnitus,and to explore its mechanism in tinnitus generation.Methods:1)Male adult Sprague-Dawley rats were randomly grouped,and received acute administration of salicylate in different doses and chronic administration.Tinnitus-like behavior was detected via the combination of the Gap pre-pulse inhibition of acoustic startle(GPIAS)and the Pre-pulse inhibition(PPI);2)several central auditory and non-auditory brain areas were sampled and analyzed with high performance liquid chromatography(HPLC)to observe the concentration of glutamate and GABA;3)Rats were performed with micro-PET scan to observe standard uptake value ratio (SUVR)of 18F-FDG and 11C-FMZ,to measure the metabolic activity and binding level of GABA_A receptor in each brain areas;4)To observe the expressions of AMPA and GABA_A receptor,chloride co-transporters and immediate early response genes(IEGs)on excitotary neuron in the auditory cortex.Results:1)No tinnitus-like behavior was detected after acute administration of salicylate.Tinnitus-like behavior were detected after 14 days'of administration of salicylate and 7days'cessation of injection after 14 days'of administration of salicylate;2)The concentration of glutamate and GABA were not altered in the auditory cortex,hippocampus,medial prefrontal cortex,cingulate gyrus,amygdala,paraflocculus, inferior colliculus and cochlear nucleus during the chronic administration and cessation of salicylate;3)The SUVR of 18F-FDG was increased in auditory and limbic system during chronic administration of salicylate.The SUVR of 11C-FMZ was increased in these areas during cessation of salicylate administration.And the above changes of cortex lasted for the longest time among all the measured brain areas;4)On the excitotary neurons of auditory cortex,the expressions of IEGs were increased,the expressions of AMPA receptors were decreased and the the expressions of GABA_Areceptor were increased after acute administration of salicylate;the expressions of c-Fos were increased,the expressions of KCC2 were decreased,and both the expressions of AMPA and GABA_A receptors were increased after chronic administration of salicylate.Conclusions:1)The increased metabolic activity and hysteretic enhanced GABA_A receptor binding in the auditory and limbic system,indicated that tinnitus generation was associated with hyperactivity of these brain areas,while the hysteretic enhanced GABA_A receptor binding was relevant to tinnitus relieving.The above changes of cortex lasted for the longest time among all the brain areas;2)The changes of AMPA and GABA_A receptors expressions on the excitotary neurons in the auditory cortex responded in a compensatory manner to acute administration of salicylate and responded in a decompensatory way to chronic administration.These evidences indicated that the excitotary neurons of the auditory cortex played crucial roles in generation and relieving of tinnitus;3)The concentration of glutamate and GABA were not altered by chronic administration of salicylate in the brain areas indicated in the current study.