Sodium Salicylate Suppresses GABAergic Inhibitory Synaptic Transmissions In The Central Auditory System

Salicytate is a major metabolic component of aspirin.Sodium salicylate(SS)is widely prescribed or sold over the counter as well as aspirin for anti-inflammation and for chronic pain relief with a side effect of tinnitus.Recently,SS is used for prevention and treatment of cardio cerebrovascular diseases for its anticoagulation effect.A large dose of SS could reliably induce the behavior manifestation of tinnitus in laboratory animals,so SS becomes a common drug for investigation into the neural mechanism of tinnitus.Previous studies have revealed that the cochlea is the pharmacological site of SS.The auditory sensitivity and selectivity can be affected by SS thourgh peripheral insults such as damaged electro-motility of outer hair cells. However,studies carried out with positron emission tomography(PET)reveal a possible central origin of tinnitus in patients.These indicate that changed activities in the central auditory system by SS might also contribute to the generation of tinnitus. Many in vivo electrophysiological experiments have indeed provided some insights into our understanding of the neural mechanisms of SS-induced tinnitus,however, these observed changes might inherit alterations occurred in either the cochlea or the central auditory neurons.The auditory system requires a delicate balance between inhibition and excitation for normal auditory perception.One theory holds that tinnitus might be generated if such a balance is altered by hearing loss or ototoxic drugs such as SS.The response properties of central auditory neurons are greatly shaped by GABAergic inhibition,and widen receptive filed and elevated excitability of auditory neurons may be caused by disinhibition.The GABAergic synaptic transmission is powerfully modulated by many neuromodulatory systems such as 5-HT (5-hydroxytryptamine),then whether raised excitability may partially result from likely altered serotonergic system by SS.In the present studies,whole cell recording techniques in the auditory cortex and inferior colliculus were applied to examine whether SS can influence the inhibitory synaptic transmission and whether serotonigeric system is involved in the SS-induced tinnitus.The major findings are as follows:1,Evoked inhibitory postsynaptic currents(eIPSCs)in response to lateral afferent stimulation and miniature postsynaptic inhibitory synaptic currents(mIPSCs)were recorded in layerⅡ/Ⅲpyramidal neurons of auditory cortex slice with whole cell recording technique.The author observed that SS itself didn't cause a change in the neuronal input resistance,but it could reversibly reduce eIPSCs in a concentration dependent manner.In addition,SS at 1.4 mM significantly reduced the amplitude of mIPSCs and frequency of mIPSCs.These results demonstrate that SS depresses the inhibitory synaptic transmission of the auditory cortex.The depression could be due to both presynaptic and postsynaptic actions of SS given the reduced frequency and amplitude of mIPSCs.This study suggests that the raised excitability of the auditory cortex due to disinhibition is probably one of the mechanisms for tinnitus induced by SS.2,Since serotonin(5-hydroxytryptamine,5-HT)containing fibers preferentially innervate inhibitory GABA neurons,there exists a possibility that SS causes the imbalance between inhibition and excitation through influencing serotonergic modulation of the GABAergic synaptic transmission.The effects of SS on 5-HT-mediated GABAergic spontaneous inhibitory postsynaptic currents(sIPSCs) from neurons of the central nucleus of rat inferior colliculus were examined with whole-cell patch-clamp technique and brain slice preparation.Perfusion of 40μM 5-HT robustly enhanced both frequency and amplitude of GABAergic sIPSCs and this 5-HT-induced enhancement of GABAergic sIPSCs could be suppressed by 1.4 mM SS.Tetrodotoxin at 0.5μM produced a similar effect as SS did,suggesting that SS suppresses the 5-HT-induced enhancement of GABAergic sIPSCs through eliminating spontaneous action potentials of GABA neurons.These findings suggest that SS may preferentially target GABA neurons and consequently interrupt a normal level of GABAergic synaptic transmissions maintained by the serotonergic system in SS-induced tinnitus.In conclusion,these findings indicate that SS has a direct effect on the central auditory system.The impaired functions of GABA neruons are suggested to contribute to SS-induced tinnitus.The present studies may provide insights into understanding the central origin of tinnitus and help us to develop an effective therapeutic strategy for chronic tinnitus.