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Neurotransmitter Modulation Relates with Tinnitus Signal Generation and Management

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Neurotransmitter Modulation Relates with Tinnitus Signal Generation and Management View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of Otology 2007 Vol. 2 No. 2 63 ·· Review Neurotransmitter Modulation Relates with Tinnitus Signal Generation and Management Wei Sun1, 2, Jianzhong Lu1, Erin Laundrie 1, 2 1 Center for Hearing and Deafness, 2 Department of Communicative Disorders and Sciences, University at Buffalo, Buffalo, NY 14214, USA Abstract Tinnitus is a subjective perception of phantom sound that currently cannot be objectively measured. However, there is growing evidence suggesting that the biological source of tinnitus may exist in one or more than one place in the auditory pathway. Recent studies have found that neurotransmitters or modulators, such as gluta- mate, γ-aminobutyric acid(GABA), serotonin, dynorphin, dopamine, neurosteroid, acetylcholine(ACh) and sub- stance P, are involved in tinnitus generation. Animal and human studies have shown that some of these neurotrans- mitters and the agonists or antagonists of their receptors either affect tinnitus behaviors or demonstrate some de- gree of treatment effects on tinnitus. However, due to the unclear biological mechanisms of tinnitus and side ef- fects of these drugs, the value of clinical usage of such drugs in treating tinnitus is yet to be established. Revealing the relationship between tinnitus and neurotransmitter receptor functions will help identify more effective drugs for tinnitus treatment. This article reviews the literature of neurophysiological studies on tinnitus in both animal and human subject studies at various levels of the auditory pathway. Key words tinnitus; auditory system; NMDA; serotonin; GABA; ACh Introduction neurotransmitters and their receptors may be a key in Tinnitus is assessed based on patient’s subjective triggering tinnitus generation. Localizing the origin description rather than pathological source due to the and cause of tinnitus using neurophysiological lack of knowledge of its mechanisms and available approach has become a critical issue in finding a objective measurement. However, there is growing treatment of tinnitus to help millions of patients who evidence suggesting that tinnitus is more than a suffer from tinnitus. The goal of this paper is to psychological hallucination. It has one or more than summarize recent findings on neurotransmitters and one physiologic source in the auditory pathway and/or neurotransmitter receptors related to tinnitus in other parts of the central nervous system. Although mechanisms and treatment. it is still not clear where tinnitus is located, e.g., in the Glutamate Receptor ear or in the brain, in the auditory system or in non-auditory systems, significant progress has been Glutamate is one of the most important excitatory made in the past ten years that links tinnitus with neurotransmitters in both peripheral and central ner- neurological changes in the brain. Since vous systems. In the inner ear, glutamate is released neurotransmitter release from neuron presynaptic by hair cells and received by the dendrites of afferent structures and the response in postsynaptic structures spiral ganglion neurons through two different types of play an important role in auditory signal generation, neurotransmitter receptors, non-NMDA and NMDA re- [1] transmission and perception, dysfunction of certain ceptors . These two receptors work as a dual receptor system. Non-NMDA receptors include the kainic acid subtype and the AMPA subtype and probably contrib- ute to the fast response of spiral ganglion neurons. Correspondence to: SUN Wei, M.D., Ph.D., Center for Hearing [2] and Deafness, Department of Communicative Disorders and NMDA receptors are likely involved in a slow effect . Sciences, University at Buffalo, Buffalo, NY 14214, USA. A peripheral tinnitus model suggests that a typical pat- E-mail: [email protected]. tern of depolarization of the afferent nerve depends on Tel: +1 716 829 2001. Fax: +1 716 829 2980 the balance of the normal synaptic function. Inner ear 64·· Journal of Otology 2007 Vol. 2 No. 2 diseases, such as presbycusis, sudden hearing loss and elevation of GAD levels in the IC in rats showing noise-induced hearing loss, may involve dysfunction of tinnitus behavior, presumably to compensate GABA cochlear-synaptic functions, causing an increase in reduction. They also found that the number of spontaneous neuronal activities. Evans found that ad- GABA-A binding sites decreased significantly in rats ministration of salicylate increased spontaneous dis- with tinnitus. These studies suggest a connection charges of auditory nerves in cats[3, 4]. The increased between decreased inhibitory activity and tinnitus spontaneous activity of afferent nerves was suggested behavior. Based on the plasticity hypothesis, studies to be a physiological source of tinnitus. Based on this aimed at increasing GABA inhibition in the central hypothesis, Ehrenberger et al studied the effect of auditory system to reduce tinnitus have been conducted caroverine(a calcium channel blocker and antagonist of in animal models. Administration of baclofen, a AMPA and NMDA receptors) on tinnitus in animal GABA-B receptor agonist, resulted in a blocking effect models[5, 6, 7]. They found that applying caroverine on on amplitude enhancement in the IC induced by noise the round window exhibited a statistically significant exposure[18]. Vigabatrin, a GABA receptor agonist used protective action in noise-induced hearing loss and tin- for treating epilepsy, was found to suppress nitus. However, Muller et al studied salicylate effects noise-induced tinnitus in rats［19］. However, in a recent on auditory nerve activity in gerbils and found that human subject study, gabapentin, which has a similar spontaneous activities in auditory nerves were signifi- chemical structure as GABA and is also used for cantly decreased or remained unchanged after salicy- treating epilepsy, failed to show a sufficient effect on late injection. They concluded that the salicylate-in- reducing tinnitus[20]. This leads to the assumption that duced increasing activities in the central auditory sys- tinnitus can arise from multiple sources and involve tem were not caused by cochlear nerve hyperactivity[8]. more than one neurotransmitter such as GABA. The peripheral tinnitus model therefore cannot fully ex- Serotonin (5-HT) Expression plain the causes of tinnitus. Serotonin is a neurotransmitter broadly expressed GABA Inhibition in the central nervous system and affects a wide range The central tinnitus model is based on the plasticity of biological and behavioral functions, such as change of the central auditory system in response to emotions, anxiety and stress. As stress and anxiety are peripheral damage. GABA, a major inhibitory common symptoms in tinnitus patients, the role of neurotransmitter in the central auditory pathway, plays serotonin in persistent distressing tinnitus has been an important role in processing acoustic stimuli[9] and studied in order to develop an effective in central reorganization after peripheral damage[10, 11, 12]. pharmacological intervention to ameliorate tinnitus. Cochlear damage induced by noise exposure or aging Studies have found that patients who are under stress can cause a decrease in glutamic acid decarboxylase normally show a low level of serotonin concentration （GAD）expression, an enzyme for GABA synthesize, in blood samples and that increasing serotonin level by in the cochlear nucleus（CN）and the inferior colliculus taking serotonin reuptake inhibitor types of drugs （IC）［13, 14, 15］. GABA concentration changes can affect lessens symptoms in some patients［ ２１］. Sachanska et auditory signal processing including tuning curve, al. tested blood serotonin concentration in patients with filtering, masking and amplification in the central and without tinnitus ［22］. They found that tinnitus auditory system. Syka reported that acute noise patients showed significantly higher serotonin values exposure induced an increase of middle latency in their blood than those without tinnitus[22]. In animal responses recorded from the auditory cortex (AC) studies, Liu et al. found that salicylate(350 mg/kg, i.p.) which might be related to damage of the GABA induced a dramatic increase of serotonin levels in both inhibitory system[16]. Suneje et al found a depressed the IC and the AC. They also found exceeding levels of GABA release several days after bilateral removal of glucose and lactate, suggesting an increase of neuronal the ossicles and elevated GABA release 4 months after activity in the brain ［23］. This study implies that middle ear removal ［12］. Bauer et al studied GAD increased serotonin levels induced by salicylate may expression and binding characteristics of GABA-A relate to neuronal activity changes and tinnitus. This receptors in the auditory brainstem in rats after tinnitus may explain why some antidepressant drugs, most of was induced by salicylate［17］. They found a significant them serotonin reuptake inhibitors, may provoke or Journal of Otology 2007 Vol. 2 No. 2 65 ·· worsen tinnitus rather than lessen it［24］. The relationship memory, behavior and neuroprotection. Neurosteroids, between tus and stress and the role of serotonin such as pregnenolone and dexamethasone, have been expressiontinni in these conditions need to be clarified. used in clinical treatment of inner ear diseases, such as ［36, 37］ Dynorphin, Dopamine and Efferent Systems sudden sensorineural hearing loss , Meniere’s dis- ease［38, 39］ as well as tinnitus［40,
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