Salicylate-induced Changes Research Articles

Neuroprotective Effect of Valproic Acid on Salicylate-Induced Tinnitus.

High-dose salicylate induces temporary moderate hearing loss and the perception of a high-pitched tinnitus in humans and animals. Previous studies demonstrated that high doses of salicylate increase N-methyl-d-aspartate (NMDA) receptor levels, resulting in a rise in Ca2+ influx and induction of excitotoxicity. Glutamate excitotoxicity is associated with failure in the maintenance of calcium homeostasis, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Valproic acid (VPA) is widely used for the management of bipolar disorder, epilepsy, and migraine headaches, and is known to regulate NMDA receptor activity. In this study, we examined the beneficial effects of VPA in a salicylate-induced tinnitus model in vitro and in vivo. Cells were pretreated with VPA followed by salicylate treatment. The expression levels of NMDA receptor subunit NR2B, phosphorylated cAMP response element-binding protein—an apoptosis marker, and intracellular levels of ROS were measured using several biochemical techniques. We observed increased expression of NR2B and its related genes TNFα and ARC, increased intracellular ROS levels, and induced expression of cleaved caspase-3. These salicylate-induced changes were attenuated in the neuronal cell line SH-SY5Y and rat cortical neurons after VPA pretreatment. Together, these results provide evidence of the beneficial effects of VPA in a salicylate-induced temporary hearing loss and tinnitus model.

Salicylate-induced changes in organ of Corti vibrations

Intra organ of Corti (OC) vibrations differ from those measured at the basilar membrane (BM), with higher amplitudes and a wide-band nonlinearity extending well below a region’s best frequency. The vibrations are boosted by the cochlear amplifier, the active processes within the mammalian hearing organ, and are thus sensitive to metabolic or pharmacological manipulation. We introduced salicylate, a known blocker of outer hair cell (OHC) based electromotility, into the perilymphatic space by applying sodium salicylate onto the round window membrane. Vibration patterns of an area of the OC were mapped with phase sensitive optical coherence tomography before and after treatment; distortion product otoacoustic emissions (DPOAEs) were measured at similar times to assess the cochlear condition. Following treatment, all regions showed a loss of vibration amplitude and tuning while OHC-region vibrations retained their wide-band nonlinearity. OC vibrations, which had been relatively confined in a region including OHCs and extending to the BM at the outer pillar foot, became less confined with structures lateral to the OHCs sometimes exhibiting the highest amplitudes. Vibrations and DPOAEs could recover to baseline levels over approximately three hours post treatment.This article is part of the Special Issue Outer hair cell Edited by Joseph Santos-Sacchi and Kumar Navaratnam

Salicylate-Induced Changes in Hearing Thresholds in Mongolian Gerbils Are Correlated With Tinnitus Frequency but Not With Tinnitus Strength.

Tinnitus is an auditory phantom percept without external sound sources. Despite the high prevalence and tinnitus-associated distress of affected patients, the pathophysiology of tinnitus remains largely unknown, making prevention and treatments difficult to develop. In order to elucidate the pathophysiology of tinnitus, animal models are used where tinnitus is induced either permanently by noise trauma or transiently by the application of salicylate. In a model of trauma-induced tinnitus, we have suggested a central origin of tinnitus-related development of neuronal hyperactivity based on stochastic resonance (SR). SR refers to the physiological phenomenon that weak subthreshold signals for given sensors (or synapses) can still be detected and transmitted if appropriate noise is added to the input of the sensor. The main objective of this study was to characterize the neurophysiological and behavioral effects during salicylate-induced tinnitus and compare these to the conditions within the trauma model. Our data show, in line with the pharmacokinetics, that hearing thresholds generally increase 2 h after salicylate injections. This increase was significantly stronger within the region of best hearing compared to other frequencies. Furthermore, animals showed behavioral signs of tinnitus during that time window and frequency range as assessed by gap prepulse inhibition of the acoustic startle reflex (GPIAS). In contrast to animals with noise trauma-induced tinnitus, salicylate-induced tinnitus animals showed no correlation between hearing thresholds and behavioral signs of tinnitus, indicating that the development of tinnitus after salicylate injection is not based on SR as proposed for the trauma model. In other words, salicylate-induced tinnitus and noise trauma-induced tinnitus are not based on the same neurophysiological mechanism.

Long-term Administration of Salicylate-induced Changes in BDNF Expression and CREB Phosphorylation in the Auditory Cortex of Rats.

Hypothesis:We investigated whether salicylate induces tinnitus through alteration of the expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, tyrosine kinase receptor B (TrkB), cAMP-responsive element-binding protein (CREB), and phosphorylated CREB (p-CREB) in the auditory cortex (AC).Background:Salicylate medication is frequently used for long-term treatment in clinical settings, but it may cause reversible tinnitus. Salicylate-induced tinnitus is associated with changes related to central auditory neuroplasticity. Our previous studies revealed enhanced neural activity and ultrastructural synaptic changes in the central auditory system after long-term salicylate administration. However, the underlying mechanisms remained unclear.Methods:Salicylate-induced tinnitus-like behavior in rats was confirmed using gap prepulse inhibition of acoustic startle and prepulse inhibition testing, followed by comparison of the expression levels of BDNF, proBDNF, TrkB, CREB, and p-CREB. Synaptic ultrastructure was observed under a transmission electron microscope.Results:BDNF and p-CREB were upregulated along with ultrastructural changes at the synapses in the AC of rats treated chronically with salicylate (p < 0.05, compared with control group). These changes returned to normal after 14 days of recovery (p > 0.05).Conclusion:Long-term administration of salicylate increased BDNF expression and CREB activation, upregulated synaptic efficacy, and changed synaptic ultrastructure in the AC. There may be a relationship between these factors and the mechanism of tinnitus.

Salicylate-Induced Suppression of Electrically Driven Activity in Brain Slices from the Auditory Cortex of Aging Mice.

The prevalence of tinnitus is known to increase with age. The age-dependent mechanisms of tinnitus may have important implications for the development of new therapeutic treatments. High doses of salicylate can be used experimentally to induce transient tinnitus and hearing loss. Although accumulating evidence indicates that salicylate induces tinnitus by directly targeting neurons in the peripheral and central auditory systems, the precise effect of salicylate on neural networks in the auditory cortex (AC) is unknown. Here, we examined salicylate-induced changes in stimulus-driven laminar responses of AC slices with salicylate superfusion in young and aged senescence-accelerated-prone (SAMP) and -resistant (SAMR) mice. Of the two strains, SAMP1 is known to be a more suitable model of presbycusis. We recorded stimulus-driven laminar local field potential (LFP) responses at multi sites in AC slice preparations. We found that for all AC slices in the two strains, salicylate always reduced stimulus-driven LFP responses in all layers. However, for the amplitudes of the LFP responses, the two senescence-accelerated mice (SAM) strains showed different laminar properties between the pre- and post-salicylate conditions, reflecting strain-related differences in local circuits. As for the relationships between auditory brainstem response (ABR) thresholds and the LFP amplitude ratios in the pre- vs. post-salicylate condition, we found negative correlations in layers 2/3 and 4 for both older strains, and in layer 5 (L5) in older SAMR1. In contrast, the GABAergic agonist muscimol (MSC) led to positive correlations between ABR thresholds and LFP amplitude ratios in the pre- vs. post-MSC condition in younger SAM mice from both strains. Further, in younger mice, salicylate decreased the firing rate in AC L4 pyramidal neurons. Thus, salicylate can directly reduce neural excitability of L4 pyramidal neurons and thereby influence AC neural circuit activity. That we observed age-dependent effects of salicylate and varied GABAergic sensitivity in the AC among mouse strains with hearing loss implies that potential therapeutic mechanisms for tinnitus may operate differently in young vs. aged subjects. Therefore, scientists developing new therapeutic modalities for tinnitus treatment should consider using both aged and young animals.

Effects of the cannabinoid CB1 agonist ACEA on salicylate ototoxicity, hyperacusis and tinnitus in guinea pigs

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2′-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6–10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Salicylate-induced hyperacusis in rats: Dose- and frequency-dependent effects

The use of auditory reaction time is a reliable measure of loudness perception in both animals and humans with reaction times (RT) decreasing with increasing stimulus intensity. Since abnormal loudness perception is a common feature of hyperacusis, a potentially debilitating auditory disorder in which moderate-intensity sounds are perceived as uncomfortable or painfully loud, we used RT measures to assess rats for salicylate-induced hyperacusis. A previous study using an operant conditioning RT procedure found that high-dose sodium salicylate (SS) induced hyperacusis-like behavior, i.e., faster than normal RTs to moderate and high level sounds, when rats were tested with broadband noise stimuli. However, it was not clear from that study if salicylate induces hyperacusis-like behavior in a dose- or frequency-dependent manner. Therefore, the goals of the current study were to determine how RT-intensity functions were altered by different doses of salicylate, and, using tone bursts, to determine if salicylate induces hyperacusis-like behavior across the entire frequency spectrum or only at certain frequencies. Similar to previous physiological studies, we began to see faster than normal RTs for sounds 60 dB SPL and greater with salicylate doses of 150 mg/kg and higher; indicating the rats were experiencing hyperacusis at high salicylate doses. In addition, high-dose salicylate significantly reduced RTs across all stimulus frequencies tested which suggests that a central neural excitability mechanism may be a potential driver of salicylate-induced changes in loudness perception and hyperacusis.

DNA methylation of the prestin gene and outer hair cell electromotileresponse of the cochlea in salicylate administration

Background/aim: Activity of the prestin gene may have a role in the pathogenesis of salicylate-induced ototoxicity. We investigated DNA methylation for prestin gene exon 1 in salicylate-injected guinea pigs.Materials and methods: Fifteen guinea pigs (30 ears) underwent audiological evaluation including 1000 Hz probe-tone tympanometry and a distortion product otoacoustic emission (DPOAE) test. The animals were randomly divided into three groups. Groups 2 (8 ears) and 3 (14 ears) were injected with intramuscular saline and sodium salicylate (200 mg/kg), respectively twice daily for 2 weeks. Group 1 (8 ears) received no injection. DPOAE measurements were performed at baseline; after 1, 2, 4, and 8 h (acute effect); and after 1 and 2 weeks (chronic effect). After audiological measurements, the animals were sacrificed for DNA isolation.Results: While a significant decrease (P < 0.01) was found for the acute effect in all frequencies in Group 3 according to baseline measurements, there was no difference in terms of chronic effect. DNA methylation increased during the acute phase of salicylate administration, whereas it returned to initial levels during the chronic phase.Conclusion: Salicylate-induced changes in DPOAE responses may be related to prestin-gene methylation. These results may have important implications for salicylate ototoxicity.

Salicylate-induced changes in immediate-early genes in the hippocampal CA1 area.

Studies have suggested that salicylate affects neuronal function via interactions with specific membrane channels/receptors. However, the effect of salicylate on activity and synaptic morphology of the hippocampal Cornu Ammonis (CA) 1 area remains to be elucidated. The activation of immediate-early genes (IEGs) was reported to correlate with neuronal activity, in particular activity-regulated cytoskeleton-associated protein and early growth response gene 1. The aim of the present study was to evaluate the expression of these IEGs, as well that of N-methyl D-aspartate (NMDA) receptor subunit 2B in rats following acute and chronic salicylate treatment. Protein and messenger RNA levels of all three genes were increased in rats following chronic administration of salicylate (300 mg/kg for 10 days), returning to baseline levels 14 days post-cessation of treatment. The transient upregulation of gene expression following treatment was accompanied by ultrastructural alterations in hippocampal CA1 area synapses. An increase in synaptic interface curvature was observed as well as an increased number of presynaptic vesicles; in addition, postsynaptic densities thickened and lengthened. In conclusion, the results of the present study indicated that chronic exposure to salicylate may lead to structural alteration of hippocampal CA1 neurons, and it was suggested that this process occurs through induced expression of IEGs via NMDA receptor activation.

Salicylate Inhibits Thrombopoiesis in Rat Megakaryocytes by Changing the Membrane Micro-Architecture

Background/Aims: Salicylate causes drug-induced immune thrombocytopenia. However, some clinical studies indicate the presence of additional mechanisms in the drug-induced thrombocytopenia, by which the platelet production from megakaryocytes may directly be affected. Since salicylate is amphiphilic and preferentially partitioned into the lipid bilayers of the plasma membrane, it can induce some structural changes in the megakaryocyte membrane surface and thus affect the process of thrombopoiesis. Methods: Employing the standard patch-clamp whole-cell recording technique, we examined the effects of salicylate on the membrane capacitance in rat megakaryocytes. Taking electron microscopic imaging of the cellular surface, we also examined the effects of salicylate on the membrane micro-architecture of megakaryocytes. Results: Salicylate significantly decreased the membrane capacitance of megakaryocytes, indicating the decreased number of invaginated plasma membranes, which was not detected by the fluorescent imaging technique. As shown by electron microscopy, salicylate actually halted the process of pro-platelet formation in megakaryocytes. Conclusion: This study demonstrated for the first time that salicylate inhibits the process of thrombopoiesis in megakaryocytes, as detected by the decrease in the membrane capacitance. Salicylate-induced changes in the membrane micro-architecture are thought to be responsible for its effects.

Amygdala hyperactivity and tonotopic shift after salicylate exposure

The amygdala, important in forming and storing memories of aversive events, is believed to play a major role in debilitating tinnitus and hyperacusis. To explore this hypothesis, we recorded from the lateral amygdala (LA) and auditory cortex (AC) before and after treating rats with a dose of salicylate that induces tinnitus and hyperacusis-like behavior. Salicylate unexpectedly increased the amplitude of the local field potential (LFP) in the LA making it hyperactive to sounds≥60 dB SPL. Frequency receptive fields (FRFs) of multiunit (MU) clusters in the LA were also dramatically altered by salicylate. Neuronal activity at frequencies below 10 kHz and above 20 kHz was depressed at low intensities, but was greatly enhanced for stimuli between 10 and 20 kHz (frequencies near the pitch of the salicylate-induced tinnitus in the rat). These frequency-dependent changes caused the FRF of many LA neurons to migrate towards 10-20 kHz thereby amplifying activity from this region. To determine if salicylate-induced changes restricted to the LA would remotely affect neural activity in the AC, we used a micropipette to infuse salicylate (20 μl, 2.8 mM) into the amygdala. Local delivery of salicylate to the amygdala significantly increased the amplitude of the LFP recorded in the AC and selectively enhanced the neuronal activity of AC neurons at the mid-frequencies (10-20 kHz), frequencies associated with the tinnitus pitch. Taken together, these results indicate that systemic salicylate treatment can induce hyperactivity and tonotopic shift in the amygdala and infusion of salicylate into the amygdala can profoundly enhance sound-evoked activity in AC, changes likely to increase the perception and emotional salience of tinnitus and loud sounds. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Salicylate induced neural changes in the primary auditory cortex of awake cats

Systemic administration of salicylate at high doses can induce reversible tinnitus and hyperacusis in humans and animals. For this reason, a number of studies have investigated the salicylate-induced changes of neural activity in the auditory cortex (AC); however, most previous studies of the AC were conducted on brain slices or anesthetized animals, which cannot completely represent the actual conditions. Few efforts have been made to examine the neural activity of awake animals, and only recorded the local field potential (LFP) of the AC. In this study, we recorded neural spike activities from chronically implanted electrodes in the primary AC (A1) of awake cats, and investigated the changes of neural responses to pure-tone and click-train stimuli after systemic injection of 200 mg/kg salicylate. We found that sound-evoked spike activities were significantly increased from 1 h after salicylate administration, and the increase of neural responses lasted longer than 3 days with a peak at 12 h. Salicylate not only increased the amplitude of transient responses at the onset and offset of pure-tone stimuli, but also induced a sustained response during the prolonged stimulus period and a late response at ∼100 ms after stimulus offset. The significant enhancement of neural responses was observed over the entire tested frequency range (0.1–16 kHz) with a relative peak in the band of 3.2–9.6 kHz. The capability of exhibiting spikes synchronizing with successive clicks was also enhanced. All these effects were more apparent when the neurons were driven by high intensity sounds. Salicylate-administration also decreased the mean spontaneous rate in A1 units, and the decrease of spontaneous rate was larger in the units with a high initial spontaneous rate. Our data confirm that salicylate can modulate the neural activity at the cortical level and provide more information for understanding the mechanism of salicylate-induced tinnitus.

Salicylate-induced modification of plant proteomes (review)

Here we present a brief review of the reports concerning proteome modifications under the influence of salicylic acid, which is one of the major mediators of both local and systemic immunity. We describe also the results of our own studies of the salicylate-induced changes in proteomes of pea leaves and roots. Fifteen salicylate-inducible proteins, which were previously unknown, have been identified. Unlike the roots, leaves accumulated some chloroplast proteins and enzymes capable of degrading the pathogen cell walls. In the roots, salicylic acid increased the content of enzymes, improving the resistance of plant cells themselves, and promoted the disappearance of reductase of oxophytodienic acid. The latter could lead to inhibition of jasmonic acid synthesis and stimulation of local immunity. High (apoptotic) concentration of salicylic acid intensified synthesis of root proteins involved in the formation of heteroprotein complexes, which play an important role in the functioning of the signaling system, DNA synthesis and repair, and protein synthesis, refolding, and proteolysis.

Gap Detection Methods for Assessing Salicylate-Induced Tinnitus and Hyperacusis in Rats

A variety of options for behavioral assessment of tinnitus in laboratory animals are available to researchers today. These options are briefly reviewed, followed by data suggesting that gap detection procedures might be used to efficiently measure acute, salicylate-induced tinnitus and possibly hyperacusis in rats. Fischer Brown Norway rats (n = 10) were given intraperitoneal injections of 350 mg/kg sodium salicylate on 2 consecutive days, and the effects on gap detection were observed across 9 different frequency bands. Pretest, posttest, and washout data were collected. An additional 4 rats were each given 4 different doses of sodium salicylate (0, 150, 250, and 300 mg/kg), and gap detection and prepulse inhibition were measured. Significant gap detection deficits were observed from pre- to posttest that were consistent with tinnitus. Consistent gap detection deficits were found using broadband noise backgrounds, while significant improvements in responding to frequency-specific test bands were found. Similar effects were repeated in the dose response portion of the study. Gap detection procedures efficiently measured salicylate-induced changes in behavior that were consistent with the presence of tinnitus. In addition, the reliable, stronger responses at many frequencies after salicylate injections suggest the possibility of measuring a hyperacusis-like phenomenon using these methods.

Midazolam Reverses Salicylate-Induced Changes in Brain-Derived Neurotrophic Factor and Arg3.1 Expression: Implications for Tinnitus Perception and Auditory Plasticity

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, however, has 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 reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemistry, the expression of these genes was monitored in the rat auditory system after local (cochlear) and systemic application of salicylate. Induction of tinnitus and hearing loss was verified in a behavioral 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. 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 GABAergic inhibition of cochlear neurons in the modulation of Arg3.1 plasticity changes in the auditory cortex and tinnitus perception.

Salicylate Alters the Expression of Calcium Response Transcription Factor 1 in the Cochlea: Implications for Brain-Derived Neurotrophic Factor Transcriptional Regulation

Brain-derived neurotrophic factor (BDNF) is a key neurotrophin whose expression is altered in response to neurological activity, influencing both short- and long-term synaptic changes. The BDNF gene consists of eight upstream exons (I-VII), each of which has a distinct promoter and can be independently spliced to the ninth coding exon (IX). We showed recently that the expression of BDNF exon IV in the cochlea is altered after exposure to salicylate, an ototoxic drug that in high doses is able to induce hearing loss and tinnitus. These changes were a crucial trigger for plasticity changes in the central auditory system. BDNF exon IV expression is regulated via interaction between calcium-response elements CaRE1, CaRE2, and CaRE3/Cre (CaREs) that are bound by the transcription factors CaRF1, upstream stimulatory factors 1 and 2 (USF1/2), and cAMP/Ca(2+) response element-binding protein (CREB), respectively. To determine whether the salicylate-induced changes in cochlear BDNF exon IV expression include a differential use of the CaRE binding proteins, we studied the level of the corresponding binding proteins in the spiral ganglion neurons before and after systemic application of concentrated salicylate using in situ hybridization and RT-PCR. BDNF exon IV and CaRF1 expression were up-regulated after application of salicylate, whereas USF1/2 and CREB mRNA expression remained unaffected. The changes in BDNF exon IV and CaRF1 expression were also dose-dependent. The data show Ca(2+) and CaRF1 as messengers of trauma (salicylate)-induced altered BDNF levels in the cochlea. Furthermore, they also provide the first evidence that a differential regulation of BDNF transcription factors might participate in BDNF-mediated plasticity changes.

Salicylate-induced changes in auditory thresholds of adolescent and adult rats.

Shifts in auditory intensity thresholds after salicylate administration were examined in postweanling and adult pigmented rats at frequencies ranging from 1 to 35 kHz. A total of 132 subjects from both age levels were tested under two-way active avoidance or one-way active avoidance paradigms. Estimated thresholds were inferred from behavioral responses to presentations of descending and ascending series of intensities for each test frequency value. Reliable threshold estimates were found under both avoidance conditioning methods, and compared to controls, subjects at both age levels showed threshold shifts at selective higher frequency values after salicylate injection, and the extent of shifts was related to salicylate dose level.

Exogenous calcium protects postweanling rats from salicylate-induced changes in auditory conditioning

During Days 26–32 (postnatal), 18 rats drank more of a 0.05-M calcium-enriched solution when it was given to them ad lib or 1 h daily, but not when it was given 15 min daily, compared with 18 pups with similar access to plain water only. In a second experiment, acquisition and extinction of auditory conditioned suppression were observed in thirty-six 25-day-old pups, half of them reared with the calcium supplement throughout gestation and preweanling, and the other half reared with tap water. Twenty-two hours before training, the subjects were fluid deprived and exposed to continuous noise of 60 dB (SPL). Two hours prior to each session, the subjects received either injections of sodium salicylate before both sessions (n = 6 for each fluid type), saline before acquisition and salicylate before the extinction session (n= 6), or saline before both sessions (n = 6). Suppression of the approach to drink at the end of an alleyway paired the offset of the 60-dB noise and footshock. Calcium afforded subjects protection from salicylate-induced changes in auditory behavior during both acquisition and extinction.

Salicylate-induced changes in cat auditory nerve activity.

The purpose of this study was to measure, in the cat, spontaneous auditory nerve (AN) activity before and after injection with sodium salicylate. Ten cats were anesthetized, and the AN and round window (RW) were surgically exposed. Electrodes were applied to allow recording from three channels, including bipolar electrodes and monopolar electrodes located directly on the auditory nerve, in addition to an RW electrode. Spectral averaging of the spontaneous activity was performed before and during salicylate treatment. An increase in spectral activity near 200 Hz was noted in all cats by 3 hours after salicylate injection. This activity was present in bipolar, monopolar, and RW records, and was temporarily diminished or eliminated by injection of lidocaine. No such spectral changes were found in saline-injected control animals. These results show promise of developing a noninvasive, objective, quantitative measure of tinnitus for studies in animals and in man.

Salicylate-induced changes in spontaneous activity of single units in the inferior colliculus of the guinea pig.

Changes in spontaneous neuronal activity of the inferior colliculus in albino guinea pigs before and after administration of sodium salicylate were analyzed. Animals were anesthetized with pentobarbital, and two microelectrodes separated by a few hundred microns were driven through the inferior colliculus. After collecting a sufficiently large sample of cells, sodium salicylate (450 mg/kg) was injected i.p. and recordings again made 2 h after the injection. Comparison of spontaneous activity recorded before and after salicylate administration revealed highly statistically significant differences (p less than 0.001). After salicylate, the mean rate of the cell population increased from 29 to 83 Hz and the median from 26 to 74 Hz. Control experiments in which sodium salicylate was replaced by saline injection revealed no statistically significant differences in cell discharges. Recordings made during the same experiments from lobulus V of the cerebellar vermis revealed no changes in response to salicylate. The observed changes in single-unit activity due to salicylate administration may represent the first systematic evidence of a tinnituslike phenomenon in animals.