Doses Of Sodium Salicylate Research Articles

Identifying tinnitus in mice by tracking the motion of body markers in response to an acoustic startle.

Rodent models of tinnitus are commonly used to study its mechanisms and potential treatments. Tinnitus can be identified by changes in the gap-induced prepulse inhibition of the acoustic startle (GPIAS), most commonly by using pressure detectors to measure the whole-body startle (WBS). Unfortunately, the WBS habituates quickly, the measuring system can introduce mechanical oscillations and the response shows considerable variability. We have instead used a motion tracking system to measure the localized motion of small reflective markers in response to an acoustic startle reflex in guinea pigs and mice. For guinea pigs, the pinna had the largest responses both in terms of displacement between pairs of markers and in terms of the speed of the reflex movement. Smaller, but still reliable responses were observed with markers on the thorax, abdomen and back. The peak speed of the pinna reflex was the most sensitive measure for calculating GPIAS in the guinea pig. Recording the pinna reflex in mice proved impractical due to removal of the markers during grooming. However, recordings from their back and tail allowed us to measure the peak speed and the twitch amplitude (area under curve) of reflex responses and both analysis methods showed robust GPIAS. When mice were administered high doses of sodium salicylate, which induces tinnitus in humans, there was a significant reduction in GPIAS, consistent with the presence of tinnitus. Thus, measurement of the peak speed or twitch amplitude of pinna, back and tail markers provides a reliable assessment of tinnitus in rodents.

Sodium Salicylate as Feed Additive in Broilers: Absence of Toxicopathological Findings.

Antimicrobial growth promoters (AGPs) in animal production have been related to the increase in multidrug-resistant bacteria. The AGP ban in many countries has highlighted the growing need for alternatives for feed additives. Considering the non-antibiotic anti-inflammatory theory of AGPs, chicks received three different doses of sodium salicylate (SS) in feed (10, 30, 90 mg/kg), basal diet (BD) was used as a negative control, and zinc bacitracin (ZB) was used as a positive control. Chicks were individually housed to increase the accuracy of the dose of SS ingested. Performance parameters and footpad dermatitis were evaluated weekly, while haematology, serum biochemistry, histopathology, and tibial dyschondroplasia were determined on Days 21 and 42. A linear dose-dependent decrease in haemoglobin concentration was observed, but the values were within the normal reference range. Among all the other evaluated parameters, no relevant differences between treatments were observed; however, not even the AGP group performed better than the control group. It is possible that the conditions in which the birds were raised were not stressful enough to allow for anti-inflammatories to demonstrate their beneficial effects on performance. Studies should be conducted where the animals are exposed to commercial conditions, as the presence of natural stressors could allow a better evaluation of the efficacy of the anti-inflammatory agent as a growth promoter.

Safety and growth-promoting potential of repeated administration of sodium salicylate to broilers

Antimicrobial growth promoters (AGPs) have been banned from animal husbandry owing to their association with the occurrence of bacterial resistance. Although the mechanism of action of AGP is still unknown, it is believed to be related to an anti-inflammatory action in the gastrointestinal tract. In this context, the aim of the present study was to establish if supplementation of broiler feed with the non-steroidal anti-inflammatory sodium salicylate (SS) induces adverse effects related to this class of drug and to evaluate the potentiality of SS in improving the zootechnical indices of broilers. One-day-old Cobb 500 male chicks were divided into four groups (12 per group) and treated over a period of 42 days with non-supplemented feed (control group) or with feed to which doses of 2.5, 5.0, or 10.0 mg of SS/kg BW were added daily. Feed intake and BW were assessed and haematological, biochemical, and histopathological alterations were evaluated throughout the experiment. Whereas no statistical differences in food intake or BW were detected between the groups, a 5.8% increase in total BW gain was observed in broilers treated with 10 mg of SS/kg BW. In addition, the highest dose of SS studied generated the lowest total feed conversion rate over the experimental period in comparison with all other SS treatment groups. Haematological and biochemical evaluations did not reveal any altered parameters that could be related to the adverse effects of SS. No renal or hepatic alterations were detected in the histopathological study of tissue collected on day 42, and no lesions or ulcerations were observed in the gastrointestinal tract. We conclude that daily doses of SS in the range of 2.5–10 mg/kg BW can be added safely to broiler feed for 42 days, and that this non-steroidal anti-inflammatory drug is promising for future studies of its use as a growth-promoting agent.

Non-selective COX inhibitors impair memory formation and short-term but not long-term synaptic plasticity.

Cyclooxygenase (COX) plays a critical role in synaptic plasticity. Therefore, long-term administration of acetylsalicylic acid (ASA) and its main metabolite, salicylate, as a COX inhibitor may impair synaptic plasticity and subsequently memory formation. Although different studies have tried to explain the effects of ASA and sodium salicylate (SS) on learning and memory, the results are contradictory and the mechanisms are not exactly known. The present study was designed to investigate the effects of long-term low-dose (equivalent to prophylactic dose) and short-term high-dose (equivalent to analgesic dose) administration of ASA and SS respectively, on spatial learning and memory and hippocampal synaptic plasticity. Animals were treated with a low dose of ASA (2mg/mlsolvated in drinking water, 6weeks) or a high dose of SS, a metabolite of ASA, (300mg/kg, 3days, twice-daily, i.p). Spatial memory and synaptic plasticity were assessed by water maze performance and in vivo field potential recording from CA1, respectively. Animals treated with ASA but not SS showed a significant increase in escape latency and distance moved. Furthermore, in the probe test, animals treated with both drugs spent less time in the target quadrant zone. The paired-pulse ratio (PPR) at 20-ms inter-pulse intervals (IPI) as an index of short-term plasticity in both treated groups was significantly higher than of the control group. Interestingly, none of the administered drugs affected long-term potentiation (LTP). These data suggested that long-term inhibition of COX disrupted memory acquisition and retrieval. Interestingly, cognitive impairments happened along with short-term but not long-term synaptic plasticity disturbance.

Salicylate decreases the spontaneous firing rate of guinea pig auditory nerve fibres

Tinnitus has similarities to chronic neuropathic pain where there are changes in the firing rate of different types of afferent neurons. We postulated that one possible cause of tinnitus is a change in the distribution of spontaneous firing rates in at least one type of afferent auditory nerve fibre in anaesthetised guinea pigs. In control animals there was a bimodal distribution of spontaneous rates, but the position of the second mode was different depending upon whether the fibres responded best to high (> 4 kHz) or low (≤4 kHz) frequency tonal stimulation. The simplest and most reliable way of inducing tinnitus in experimental animals is to administer a high dose of sodium salicylate. The distribution of the spontaneous firing rates was different when salicylate (350 mg/kg) was administered, even when the sample was matched for the distribution of characteristic frequencies in the control population. The proportion of medium spontaneous rate fibres (MSR, 1≤ spikes/s ≤20) increased while the proportion of the highest, high spontaneous firing rate fibres (HSR, > 80 spikes/s) decreased following salicylate. The median rate fell from 64.7 spikes/s (control) to 35.4 spikes/s (salicylate); a highly significant change (Kruskal-Wallis test p < 0.001). When the changes were compared with various models of statistical probability, the most accurate model was one where most HSR fibres decreased their firing rate by 32 spikes/s. Thus, we have shown a reduction in the firing rate of HSR fibres that may be related to tinnitus.

Plasticity in Limbic Regions at Early Time Points in Experimental Models of Tinnitus.

Tinnitus is one of the most prevalent auditory disorders worldwide, manifesting in both chronic and acute forms. The pathology of tinnitus has been mechanistically linked to induction of harmful neural plasticity stemming from traumatic noise exposure, exposure to ototoxic medications, input deprivation from age-related hearing loss, and in response to injuries or disorders damaging the conductive apparatus of the ears, the cochlear hair cells, the ganglionic cells of the VIIIth cranial nerve, or neurons of the classical auditory pathway which link the cochlear nuclei through the inferior colliculi and medial geniculate nuclei to auditory cortices. Research attempting to more specifically characterize the neural plasticity occurring in tinnitus have used a wide range of techniques, experimental paradigms, and sampled at different windows of time to reach different conclusions about why and which specific brain regions are crucial in the induction or ongoing maintenance of tinnitus-related plasticity. Despite differences in experimental methodologies, evidence reveals similar findings that strongly suggest that immediate and prolonged activation of non-classical auditory structures (i.e., amygdala, hippocampus, and cingulate cortex) may contribute to the initiation and development of tinnitus in addition to the ongoing maintenance of this devastating condition. The overarching focus of this review, therefore, is to highlight findings from the field supporting the hypothesis that abnormal early activation of non-classical sensory limbic regions are involved in tinnitus induction, with activation of these regions continuing to occur at different temporal stages. Since initial/early stages of tinnitus are difficult to control and to quantify in human clinical populations, a number of different animal paradigms have been developed and assessed in experimental investigations. Reviews of traumatic noise exposure and ototoxic doses of sodium salicylate, the most prevalently used animal models to induce experimental tinnitus, indicate early limbic system plasticity (within hours, minutes, or days after initial insult), supports subsequent plasticity in other auditory regions, and contributes to the pathophysiology of tinnitus. Understanding this early plasticity presents additional opportunities for intervention to reduce or eliminate tinnitus from the human condition.

Functional Neuroanatomy of Salicylate- and Noise-Induced Tinnitus and Hyperacusis.

Tinnitus and hyperacusis are debilitating conditions often associated with aging or exposure to intense noise or ototoxic drugs. One of the most reliable methods of inducing tinnitus is with high doses of sodium salicylate, the active ingredient in aspirin. High doses of salicylate have been widely used to investigate the functional neuroanatomy of tinnitus and hyperacusis. High doses of salicylate have been used to develop novel behavioral methods to detect the presence of tinnitus and hyperacusis in animal models. Salicylate typically induces a hearing loss of approximately 20dB which greatly reduces the neural output of the cochlea. As this weak neural signal emerging from the cochlea is sequentially relayed to the cochlear nucleus, inferior colliculus, medial geniculate, and auditory cortex, the neural response to suprathreshold sounds is progressively amplified by a factor of 2-3 by the time the signal reaches the auditory cortex, a phenomenon referred to as enhanced central gain. Sound-evoked hyperactivity also occurred in the amygdala, a region that assigns emotional significance to sensory stimuli. Resting state functional magnetic imaging of the BOLD signal revealed salicylate-induced increases in spontaneous neural activity in the inferior colliculus, medial geniculate body, and auditory cortex as well as in non-auditory areas such as the amygdala, reticular formation, cerebellum, and other sensory areas. Functional connectivity of the BOLD signal revealed increased neural coupling between several auditory areas and non-auditory areas such as the amygdala, cerebellum, reticular formation, hippocampus, and caudate/putamen; these strengthened connections likely contribute to the multifaceted dimensions of tinnitus. Taken together, these results suggest that salicylate-induced tinnitus disrupts a complex neural network involving many auditory centers as well as brain regions involved with emotion, arousal, memory, and motor planning. These extra-auditory centers embellish the basic auditory percepts that results in tinnitus and which may also contribute to hyperacusis.

Sodium salicylate alters temporal integration measured through increasing stimulus presentation rates

Objective: High doses of sodium salicylate (SS) are known to induce tinnitus, general hyperexcitability in the central auditory system, and to cause mild hearing loss. We used the auditory brainstem response (ABR) to assess the effects of SS on auditory sensitivity and temporal processing in the auditory nerve and brainstem. ABRs were evoked using tone burst stimuli varying in frequency and intensity with presentation rates from 11/s to 81/s.Design: ABRs were recorded and analysed prior to and after SS treatment in each animal, and peak 1 and peak 4 amplitudes and latencies were determined along with minimal response threshold.Study Sample: Nine young adult CBA/CaJ mice were used in a longitudinal within-subject design.Results: No measurable effects of presentation rate were found on ABR threshold prior to SS; however, following SS administration increasing stimulus rates lowered ABR thresholds by as much as 10 dB and compressed the peak amplitude by intensity level functions.Conclusions: These results suggest that SS alters temporal integration and compressive nonlinearity, and that varying the stimulus rate of the ABR may prove to be a useful diagnostic tool in the study of hearing disorders that involve hyperexcitability.

Aberrant thalamocortical coherence in an animal model of tinnitus.

Electrophysiological and imaging studies from humans suggest that the phantom sound of tinnitus is associated with abnormal thalamocortical neural oscillations (dysrhythmia) and enhanced gamma band activity in the auditory cortex. However, these models have seldom been tested in animal models where it is possible to simultaneously assess the neural oscillatory activity within and between the thalamus and auditory cortex. To explore this issue, we used multichannel electrodes to examine the oscillatory behavior of local field potentials recorded in the rat medial geniculate body (MBG) and primary auditory cortex (A1) before and after administering a dose of sodium salicylate (SS) that reliably induces tinnitus. In the MGB, SS reduced theta, alpha, and beta oscillations and decreased coherence (synchrony) between electrode pairs in theta, alpha, and beta bands but increased coherence in the gamma band. Within A1, SS significantly increased gamma oscillations, decreased theta power, and decreased coherence between electrode pairs in theta and alpha bands but increased coherence in the gamma band. When coherence was measured between one electrode in the MGB and another in A1, SS decreased coherence in beta, alpha, and theta bands but increased coherence in the gamma band. SS also increased cross-frequency coupling between the phase of theta oscillations in the MGB and amplitude of gamma oscillations in A1. Altogether, our results suggest that SS treatment fundamentally alters the manner in which thalamocortical circuits communicate, leading to excessive cortical gamma power and synchronization, neurophysiological changes implicated in tinnitus. Our data provide support for elements of both the thalamocortical dysrhythmia (TD) and synchronization by loss of inhibition (SLIM) models of tinnitus, demonstrating that increased cortical gamma band activity is associated with both enhanced theta-gamma coupling as well as decreases alpha power/coherence between the MGB and A1. NEW & NOTEWORTHY There are no effective drugs to alleviate the phantom sound of tinnitus because the physiological mechanisms leading to its generation are poorly understood. Neural models of tinnitus suggest that it arises from abnormal thalamocortical oscillations, but these models have not been extensively tested. This article identifies abnormal thalamocortical oscillations in a drug-induced tinnitus model. Our findings open up new avenues of research to investigate whether cellular mechanisms underlying thalamocortical oscillations are causally linked to tinnitus.

Testing the Central Gain Model: Loudness Growth Correlates with Central Auditory Gain Enhancement in a Rodent Model of Hyperacusis

The central gain model of hyperacusis proposes that loss of auditory input can result in maladaptive neuronal gain increases in the central auditory system, leading to the over-amplification of sound-evoked activity and excessive loudness perception. Despite the attractiveness of this model, and supporting evidence for it, a critical test of the central gain theory requires that changes in sound-evoked activity be explicitly linked to perceptual alterations of loudness. Here we combined an operant conditioning task that uses a subject’s reaction time to auditory stimuli to produce reliable measures of loudness growth with chronic electrophysiological recordings from the auditory cortex and inferior colliculus of awake, behaviorally-phenotyped animals. In this manner, we could directly correlate daily assessments of loudness perception with neurophysiological measures of sound encoding within the same animal. We validated this novel psychophysical-electrophysiological paradigm with a salicylate-induced model of hearing loss and hyperacusis, as high doses of sodium salicylate reliably induce temporary hearing loss, neural hyperactivity, and auditory perceptual disruptions like tinnitus and hyperacusis. Salicylate induced parallel changes to loudness growth and evoked response-intensity functions consistent with temporary hearing loss and hyperacusis. Most importantly, we found that salicylate-mediated changes in loudness growth and sound-evoked activity were correlated within individual animals. These results provide strong support for the central gain model of hyperacusis and demonstrate the utility of using an experimental design that allows for within-subject comparison of behavioral and electrophysiological measures, thereby making inter-subject variability a strength rather than a limitation.

Enhancement of Endocannabinoid-dependent Depolarization-induced Suppression of Excitation in Glycinergic Neurons by Prolonged Exposure to High Doses of Salicylate

The Dorsal Cochlear Nucleus (DCN) is a region which has been traditionally linked to the genesis of tinnitus, the constant perception of a phantom sound. Sodium salicylate, a COX-2 inhibitor, can induce tinnitus in high doses. Hyperactivity of DCN neurons is observed in several animal models of tinnitus, including salicylate-induced tinnitus. The DCN presents several forms of endocannabinoid (EC)-dependent synaptic plasticity and COX-2 can also participate in the oxidative degradation of ECs. We recently demonstrated that short-term perfusion of sodium salicylate and other inhibitors of both oxidative and hydrolytic EC degradation did not affect depolarization-induced suppression of excitation (DSE), a form of EC-dependent short-term synaptic plasticity. Here, we show that prolonged incubation with high doses of sodium salicylate (1.4 mM) enhances DSE of synapses onto glycinergic DCN interneurons but not those innervating glutamatergic DCN fusiform neurons. This effect was not reproduced with lower doses of salicylate (140 µM) or with ibuprofen, another inhibitor of COX-2. This effect was not observed in the presence of AM251, an antagonist/inverse agonist of cannabinoid CB1 receptors, showing that it was dependent on EC release. Finally we demonstrated that incubation with salicylate potentiated the increase in intracellular calcium during the depolarization. Our results point to an increased inhibition of DCN inhibitory CW neuron during depolarizations, probably by an enhanced EC release during the depolarizations, which is potentially significant for DCN hyperactivity and tinnitus generation.

Reductions in cortical alpha activity, enhancements in neural responses and impaired gap detection caused by sodium salicylate in awake guinea pigs.

Tinnitus chronically affects between 10–15% of the population but, despite its prevalence, the underlying mechanisms are still not properly understood. One experimental model involves administration of high doses of sodium salicylate, as this is known to reliably induce tinnitus in both humans and animals. Guinea pigs were implanted with chronic electrocorticography (ECoG) electrode arrays, with silver‐ball electrodes placed on the dura over left and right auditory cortex. Two more electrodes were positioned over the cerebellum to monitor auditory brainstem responses (ABRs). We recorded resting‐state and auditory evoked neural activity from awake animals before and 2 h following salicylate administration (350 mg/kg; i.p.). Large increases in click‐evoked responses (> 100%) were evident across the whole auditory cortex, despite significant reductions in wave I ABR amplitudes (in response to 20 kHz tones), which are indicative of auditory nerve activity. In the same animals, significant decreases in 6–10 Hz spontaneous oscillations (alpha waves) were evident over dorsocaudal auditory cortex. We were also able to demonstrate for the first time that cortical evoked potentials can be inhibited by a preceding gap in background noise [gap‐induced pre‐pulse inhibition (PPI)], in a similar fashion to the gap‐induced inhibition of the acoustic startle reflex that is used as a behavioural test for tinnitus. Furthermore, 2 h following salicylate administration, we observed significant deficits in PPI of cortical responses that were closely aligned with significant deficits in behavioural responses to the same stimuli. Together, these data are suggestive of neural correlates of tinnitus and oversensitivity to sound (hyperacusis).

Plastic changes along auditory pathway during salicylate-induced ototoxicity: Hyperactivity and CF shifts

High dose of salicylate, the active ingredient in aspirin, has long been known to induce transient hearing loss, tinnitus and hyperacusis making it a powerful experimental tool. These salicylate-induced perceptual disturbances are associated with a massive reduction in the neural output of the cochlea. Paradoxically, the diminished neural output of the cochlea is accompanied by a dramatic increase in sound-evoked activity in the auditory cortex (AC) and several other parts of the central nervous system. Exactly where the increase in neural activity begins and builds up along the central auditory pathway are not fully understood. To address this issue, we measured sound-evoked neural activity in the cochlea, cochlear nucleus (CN), inferior colliculus (IC), and AC before and after administering a high dose of sodium salicylate (SS, 300 mg/kg). The SS-treatment abolished low-level sound-evoked responses along the auditory pathway resulting in a 20–30 dB threshold shift. While the neural output of the cochlea was substantially reduced at high intensities, the neural responses in the CN were only slightly reduced; those in the IC were nearly normal or slightly enhanced while those in the AC considerably enhanced, indicative of a progress increase in central gain. The SS-induced increase in central response in the IC and AC was frequency-dependent with the greatest increase occurring in the mid-frequency range the putative pitch of SS-induced tinnitus. This frequency-dependent hyperactivity appeared to result from shifts in the frequency receptive fields (FRF) such that the response areas of many FRF shifted/expanded toward the mid-frequencies. Our results suggest that the SS-induced threshold shift originates in the cochlea. In contrast, enhanced central gain is not localized to one region, but progressively builds up at successively higher stage of the auditory pathway either through a loss of inhibition and/or increased excitation.

Salicylate-induced hearing loss and gap detection deficits in rats.

To test the “tinnitus gap-filling” hypothesis in an animal psychoacoustic paradigm, rats were tested using a go/no-go operant gap detection task in which silent intervals of various durations were embedded within a continuous noise. Gap detection thresholds were measured before and after treatment with a dose of sodium salicylate (200 mg/kg) that reliably induces tinnitus in rats. Noise-burst detection thresholds were also measured to document the amount of hearing loss and aid in interpreting the gap detection results. As in the previous human psychophysical experiments, salicylate had little or no effect on gap thresholds measured in broadband noise presented at high-stimulus levels (30–60 dB SPL); gap detection thresholds were always 10 ms or less. Salicylate also did not affect gap thresholds presented in narrowband noise at 60 dB SPL. Therefore, rats treated with a dose of salicylate that reliably induces tinnitus have no difficulty detecting silent gaps as long as the noise in which they are embedded is clearly audible.

Non-selective NSAIDs improve the amyloid-β-mediated suppression of memory and synaptic plasticity

Alzheimer's disease (AD) is characterized by the formation of amyloid beta (Aβ) plaques in the brain. Dysfunctional excitatory synaptic transmission and neuronal plasticity are generally accepted as primary events in the development of AD. There is evidence to suggest that both COX-1 expression and COX-2 expression are changed in the brain of AD patients. However, the impact of COX-dependent mechanisms on synaptic dysfunction underlying the memory deficit is not fully elucidated. In the present study effects of non-selective NSAIDs (aspirin and sodium salicylate) on associated memory impairment as well as Aβ-mediated suppression of synaptic plasticity in the hippocampus were examined. Aβ1-42 (5μg/μl) and ibotenic acid (5μg/μl) were injected bilaterally into the dorsal hippocampus of rats and the spatial memory and long term potentiation (LTP) were assessed by water maze performance and in vivo field potential recording, respectively. Field excitatory post synaptic potentials (fEPSP) were recorded from stratum radiatum of area CA1 following Schaffer collateral stimulation. Behavioral study revealed that both sub-chronic high dose of sodium salicylate (SS) and chronic low dose of aspirin improved the spatial memory impairment of Aβ treated rats, however the effects of SS were lower than those of aspirin. Animals treated with SS and aspirin showed a significant decrease in escape latency (SS: F(1, 24)=15.85, p<0.01, aspirin: F(1, 22)=25.24, p<0.001, ANOVA). Furthermore, in probe test, animals treated with aspirin (p<0.05) but not SS (p>0.05) spent more time (one-way ANOVA) in target quadrant zone. Both applied drugs restored the suppression of fEPSP slope LTP that was induced by Aβ treatment (unpaired t-test, p<0.001). Aspirin showed a preventative effect also against Aβ-induced changes in LTP and memory task when applied before Aβ administration. Since aspirin and SS improved synaptic dysfunction, we can suggest that COX-dependent mechanisms may play a role in synaptic dysfunction in an experimental model of AD.

Forward acoustic masking enhances the auditory brainstem response in a diotic, but not dichotic, paradigm in salicylate-induced tinnitus

We recently reported that forward acoustic masking can enhance the auditory brainstem response (ABR) in rats treated with a high dose of sodium salicylate (NaSal), a tinnitus inducer, when tested in open acoustic field (Liu and Chen, 2012, Brain Research 1485, 88–94). In the present study, we first replicated this experiment in closed acoustic field under two conditions: (1) the forward masker and the probe were presented to both ears (diotic paradigm); (2) the forward masker was presented to one ear and the probe to the other ear (dichotic paradigm). We found that only when the stimuli were presented by using the diotic, rather than the dichotic, paradigm could forward acoustic masking enhance the ABR in the rat treated with NaSal (300 mg/kg). The enhancement was obvious for ABR waves II and IV, but not for wave I, indicating a central origin. The enhancement occurred at the high frequencies (16, 24, 32 kHz) at which the animals demonstrated a tinnitus-like behavior as revealed by using the gap prepulse inhibition of acoustic startle paradigm. We then administered vigabatrin, a GABA transaminase inhibitor, in the animals to suppress NaSal-induced tinnitus. The vigabatrin treatment successfully prevented forward acoustic masking from enhancing the ABR. These findings demonstrate that the observed enhancement of ABRs by forward acoustic masking originates in the central auditory pathway ipsilateral to the stimulated ear. We propose that the enhancement is closely associated with NaSal-induced tinnitus.

Adverse effects associated with high-dose acetylsalicylic acid and sodium salicylate treatment in broilers

1. Acetylsalicylic acid (ASA) and sodium salicylate (SS) are considered safe for poultry and often used in avian medicine. However, information on tolerance and specific side effects of these drugs in birds is lacking. 2. The aim of this study was to determine the effects of 14 d administration of high doses (200 or 400 mg/kg) of either ASA or SS on body weight gain, blood biochemistry, white and red blood cell counts and pathology in broilers. In addition, minimal plasma salicylate concentrations were determined on the 1st, 5th, 10th and 14th d of treatment. 3. The results showed that the dose of 400 mg/kg of either ASA or SS decreased weight gain and induced gizzard ulceration. Kidney to body weight ratio was increased in a dose-dependent manner, but serum concentrations of creatinine and uric acid were not affected. A time-dependent decrease in the minimal plasma salicylate concentration was evident.

Auditory brainstem response as a possible objective indicator for salicylate-induced tinnitus in rats

The auditory response to an acoustic stimulus will usually be suppressed, or masked, by a preceding sound. Here, we show that forward acoustic masking at a high frequency can boost the auditory brainstem response (ABR) in rats injected with a high dose of sodium salicylate (NaSal), a tinnitus inducer. The forward narrow band noise caused a decrease in the amplitude of the ABR to a probe tone burst in normal rats, but caused an unexpected increase in the amplitude at 16 kHz in rats treated with NaSal (300 mg/kg). The observed effect could be manifested in normal rats presented with a background tone added to the masker and the probe, suggesting an underlying mechanism associated with tinnitus. We hypothesize that in NaSal-treated rats, tinnitus can "internally" mask the ABR in a similar way as an external background sound does and the "unmasking" effect of forward masking can result in a rebound of the otherwise suppressed ABR. Our study raises the possibility of using the ABR as an objective indicator for NaSal-induced tinnitus in animals. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Intracortical circuits amplify sound-evoked activity in primary auditory cortex following systemic injection of salicylate in the rat

A high dose of sodium salicylate temporarily induces tinnitus, mild hearing loss, and possibly hyperacusis in humans and other animals. Salicylate has well-established effects on cochlear function, primarily resulting in the moderate reduction of auditory input to the brain. Despite decreased peripheral sensitivity and output, salicylate induces a paradoxical enhancement of the sound-evoked field potential at the level of the primary auditory cortex (A1). Previous electrophysiologic studies have begun to characterize changes in thalamorecipient layers of A1; however, A1 is a complex neural circuit with recurrent intracortical connections. To describe the effects of acute systemic salicylate treatment on both thalamic and intracortical sound-driven activity across layers of A1, we applied current-source density (CSD) analysis to field potentials sampled across cortical layers in the anesthetized rat. CSD maps were normally characterized by a large, short-latency, monosynaptic, thalamically driven sink in granular layers followed by a lower amplitude, longer latency, polysynaptic, intracortically driven sink in supragranular layers. Following systemic administration of salicylate, there was a near doubling of both granular and supragranular sink amplitudes at higher sound levels. The supragranular sink amplitude input/output function changed from becoming asymptotic at approximately 50 dB to sharply nonasymptotic, often dominating the granular sink amplitude at higher sound levels. The supragranular sink also exhibited a significant decrease in peak latency, reflecting an acceleration of intracortical processing of the sound-evoked response. Additionally, multiunit (MU) activity was altered by salicylate; the normally onset/sustained MU response type was transformed into a primarily onset response type in granular and infragranular layers. The results from CSD analysis indicate that salicylate significantly enhances sound-driven response via intracortical circuits.

GABAergic neural activity involved in salicylate-induced auditory cortex gain enhancement

Although high doses of sodium salicylate impair cochlear function, it paradoxically enhances sound-evoked activity in the auditory cortex (AC) and augments acoustic startle reflex responses, neural and behavioral metrics associated with hyperexcitability and hyperacusis. To explore the neural mechanisms underlying salicylate (SS)-induced hyperexcitability and "increased central gain," we examined the effects of GABA receptor agonists and antagonists on SS-induced hyperexcitability in the AC and startle reflex responses. Consistent with our previous findings, local or systemic application of SS significantly increased the amplitude of sound-evoked AC neural activity, but generally reduced spontaneous activity in the AC. Systemic injection of SS also significantly increased the acoustic startle reflex. S-baclofen or R-baclofen, GABA-B agonists, which suppressed sound-evoked AC neural firing rate and local field potentials, also suppressed the SS-induced enhancement of the AC field potential and the acoustic startle reflex. Local application of vigabatrin, which enhances GABA concentration in the brain, suppressed the SS-induced enhancement of AC firing rate. Systemic injection of vigabatrin also reduced the SS-induced enhancement of acoustic startle reflex. Collectively, these results suggest that the sound-evoked behavioral and neural hyperactivity induced by SS may arise from a SS-induced suppression of GABAergic inhibition in the AC.