Repeated temporary threshold shift and changes in cochlear and neural function.

A robust temporary threshold shift (TTS) can create significant primary damage to the auditory synapse, termed cochlear synaptopathy (CS). The common model applied to examination of this pathology is a single noise exposure or extended duration exposures at relatively high noise dosages. It is unclear if a single noise exposure that does not produce physiological changes consistent with CS (such as suppressed suprathreshold responses) can create evidence consistent with the pathology induced by repeated exposures. Here, we exposed 16-week (wk) old Sprague-Dawley rats to repeated noise exposures (4 consecutive days, 8-16 kHz octave-band of noise, 97 dB SPL for 2 h) and examined measures of cochlear function (distortion product otoacoustic emissions) and auditory neural integrity (auditory brainstem response, wave 1 amplitude). Our results demonstrated a mean maximal threshold shift of 16 dB at 24 h post the initial noise exposure. Subsequent daily repeated exposures (4 consecutive days) resulted in diminished threshold shift at 24 h post repeated TTS. In addition to recovered thresholds, no sustained reduction in suprathreshold responses was observed. The findings are consistent with conditioning literature suggesting diminished TTS with repeated exposures. Repeated TTS that was not individually synaptopathic did not produce physiological evidence consistent with acute CS.

Dietary supplement comprised of ß-carotene, vitamin C, vitamin E, and magnesium: failure to prevent music-induced temporary threshold shift.

This study examined potential prevention of music-induced temporary threshold shift (TTS) in normal-hearing participants. A dietary supplement composed of ß-carotene, vitamins C and E, and magnesium was assessed using a randomized, placebo-controlled, double-blind study design. Dosing began 3 days prior to the music exposure with the final dose consumed approximately 30-min pre-exposure. There were no group differences in post-exposure TTS or music-induced decreases in distortion product otoacoustic emission (DPOAE) amplitude. Transient tinnitus was more likely to be reported by the treatment group, but there were no group differences in perceived loudness or bothersomeness. All subjects were monitored until auditory function returned to pre-exposure levels. Taken together, this supplement had no effect on noise-induced changes in hearing. Recommendations for future clinical trials are discussed.

Temporary threshold shift after impulse-noise during video game play: laboratory data.

OBJECTIVE: Prevention of temporary threshold shift (TTS) after laboratory-based exposure to pure-tones, broadband noise, and narrowband noise signals has been achieved, but prevention of TTS under these experimental conditions may not accurately reflect protection against hearing loss following impulse noise. This study used a controlled laboratory-based TTS paradigm that incorporated impulsive stimuli into the exposure protocol; development of this model could provide a novel platform for assessing proposed therapeutics. DESIGN: Participants played a video game that delivered gunfire-like sound through headphones as part of a target practice game. Effects were measured using audiometric threshold evaluations and distortion product otoacoustic emissions (DPOAEs). The sound level and number of impulses presented were sequentially increased throughout the study. STUDY SAMPLE: Participants were normal-hearing students at the University of Florida who provided written informed consent prior to participation. RESULTS: TTS was not reliably induced by any of the exposure conditions assessed here. However, there was significant individual variability, and a subset of subjects showed TTS under some exposure conditions. CONCLUSIONS: A subset of participants demonstrated reliable threshold shifts under some conditions. Additional experiments are needed to better understand and optimize stimulus parameters that influence TTS after simulated impulse noise.

Relationship between noise-induced hearing-loss, persistent tinnitus and growth-associated protein-43 expression in the rat cochlear nucleus: does synaptic plasticity in ventral cochlear nucleus suppress tinnitus?

Aberrant, lesion-induced neuroplastic changes in the auditory pathway are believed to give rise to the phantom sound of tinnitus. Noise-induced cochlear damage can induce extensive fiber growth and synaptogenesis in the cochlear nucleus, but it is currently unclear if these changes are linked to tinnitus. To address this issue, we unilaterally exposed nine rats to narrow-band noise centered at 12 kHz at 126 dB sound pressure level (SPL) for 2 h and sacrificed them 10 weeks later for evaluation of synaptic plasticity (growth-associated protein 43 [GAP-43] expression) in the cochlear nucleus. Noise-exposed rats along with three age-matched controls were screened for tinnitus-like behavior with gap prepulse inhibition of the acoustic startle (GPIAS) before, 1-10 days after, and 8-10 weeks after the noise exposure. All nine noise-exposed rats showed similar patterns of severe hair cell loss at high- and mid-frequency regions in the exposed ear. Eight of the nine showed strong up-regulation of GAP-43 in auditory nerve fibers and pronounced shrinkage of the ventral cochlear nucleus (VCN) on the noise-exposed side, and strong up-regulation of GAP-43 in the medial ventral VCN, but not in the lateral VCN or the dorsal cochlear nucleus. GAP-43 up-regulation in VCN was significantly greater in Noise-No-Tinnitus rats than in Noise-Tinnitus rats. One Noise-No-Tinnitus rat showed no up-regulation of GAP-43 in auditory nerve fibers and only little VCN shrinkage, suggesting that auditory nerve degeneration plays a role in tinnitus generation. Our results suggest that noise-induced tinnitus is suppressed by strong up-regulation of GAP-43 in the medial VCN. GAP-43 up-regulation most likely originates from medial olivocochlear neurons. Their increased excitatory input on inhibitory neurons in VCN may possibly reduce central hyperactivity and tinnitus.

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.

Noise trauma impairs neurogenesis in the rat hippocampus.

The hippocampus, a major site of neurogenesis in the adult brain, plays an important role in memory. Based on earlier observations where exposure to high-intensity noise not only caused hearing loss but also impaired memory function, it is conceivably that noise exposure may suppress hippocampal neurogenesis. To evaluate this possibility, nine rats were unilaterally exposed for 2 h to a high-intensity, narrow band of noise centered at 12 kHz at 126 dB SPL. The rats were also screened for noise-induced tinnitus, a potential stressor which may suppress neurogenesis. Five rats developed persistent tinnitus-like behavior while the other four rats showed no signs of tinnitus. Age-matched sham controls showed no signs of hearing loss or tinnitus. The inner ear and hippocampus were evaluated for sensory hair cell loss and neurogenesis 10 weeks post-exposure. All noise exposed rats showed severe loss of sensory hair cells in the noise-exposed ear, but essentially no damage in the unexposed ear. Frontal sections from the hippocampus were immunolabeled for doublecortin to identify neuronal precursor cells, or Ki67 to label proliferating cells. Noise-exposed rats showed a significant reduction of neuronal precursors and fewer dividing cells as compared to sham controls. However, we could not detect any difference between rats with behavioral evidence of tinnitus versus rats without tinnitus. These results show for the first time that high intensity noise exposure not only damages the cochlea but also causes a significant and persistent decrease in hippocampal neurogenesis that may contribute to functional deficits in memory.

Salicylate increases the gain of the central auditory system.

High doses of salicylate, the anti-inflammatory component of aspirin, induce transient tinnitus and hearing loss. Systemic injection of 250 mg/kg of salicylate, a dose that reliably induces tinnitus in rats, significantly reduced the sound evoked output of the rat cochlea. Paradoxically, salicylate significantly increased the amplitude of the sound-evoked field potential from the auditory cortex (AC) of conscious rats, but not the inferior colliculus (IC). When rats were anesthetized with isoflurane, which increases GABA-mediated inhibition, the salicylate-induced AC amplitude enhancement was abolished, whereas ketamine, which blocks N-methyl-d-aspartate receptors, further increased the salicylate-induced AC amplitude enhancement. Direct application of salicylate to the cochlea, however, reduced the response amplitude of the cochlea, IC and AC, suggesting the AC amplitude enhancement induced by systemic injection of salicylate does not originate from the cochlea. To identify a behavioral correlate of the salicylate-induced AC enhancement, the acoustic startle response was measured before and after salicylate treatment. Salicylate significantly increased the amplitude of the startle response. Collectively, these results suggest that high doses of salicylate increase the gain of the central auditory system, presumably by down-regulating GABA-mediated inhibition, leading to an exaggerated acoustic startle response. The enhanced startle response may be the behavioral correlate of hyperacusis that often accompanies tinnitus and hearing loss.

Metabolic imaging of rat brain during pharmacologically-induced tinnitus.

Although much is known about the perceptual characteristics of tinnitus, its neural origins remain poorly understood. We investigated the pattern of neural activation in central auditory structures using positron emission tomography (PET) imaging in a rat model of salicylate-induced tinnitus. Awake rats were injected with the metabolic tracer, fluorine-18 fluorodeoxyglucose (FDG), once in a quiet state (baseline) and once during salicylate-induced tinnitus. Tinnitus was verified using a behavioral technique. Brain imaging was performed using a high-resolution microPET scanner. Rats underwent magnetic resonance imaging (MRI) and reconstructed MRI and microPET images were fused to identify brain structures. FDG activity in brain regions of interest were quantified and compared. MicroPET imaging showed that FDG activity in the frontal pole was stable between baseline and tinnitus conditions, suggesting it was metabolically inert during tinnitus. Inferior colliculi (p=0.03) and temporal cortices (p=0.003) showed significantly increased FDG activity during tinnitus relative to baseline; activity in the colliculi and temporal cortices increased by 17%+/-21% and 29%+/-20%, respectively. FDG activity in the thalami also increased during tinnitus, but the increase did not reach statistical significance (p=0.07). Our results show increased metabolic activity consistent with neuronal activation in inferior colliculi and auditory cortices of rats during salicylate-induced tinnitus. These results are the first to show that microPET imaging can be used to identify central auditory structures involved in tinnitus and suggest that microPET imaging might be used to evaluate the therapeutic potential of drugs to treat tinnitus.

PHARMACOLOGICAL TREATMENTS FOR TINNITUS: NEW AND OLD.

Subjective tinnitus, the phantom ringing or buzzing sensation that occurs in the absence of sound, affects 12-14% of adults; in some cases the tinnitus is so severe or disabling that patients seek medical treatment. However, although the economic and emotional impact of tinnitus is large, there are currently no FDA-approved drugs to treat this condition. Clinical trials are now underway to evaluate the efficacy of N-methyl-d-aspartate (NMDA) and dopamine D(2) antagonists, selective serotonin reuptake inhibitors (SSRIs), γ-aminobutyric acid (GABA) agonists and zinc dietary supplements. Previous off-label clinical studies, while not definitive, suggest that patients with severe depression may experience improvement in their tinnitus after treatment with antidepressants such as nortriptyline or sertraline. A small subpopulation of patients with what has been described as "typewriter tinnitus" have been shown to gain significant relief from the anticonvulsant carbamazepine. Preliminary studies with misoprostol, a synthetic prostaglandin E1 analogue, and sulpiride, a dopamine D(2) antagonist, have shown promise. Animal behavioral studies suggest that GABA transaminase inhibitors and potassium channel modulators can suppress tinnitus. Additionally, improvements in tinnitus have also been noted in patients taking melatonin for significant sleep disturbances. Like other complex neurological disorders, one drug is unlikely to resolve tinnitus in all patients; therapies targeting specific subgroups are likely to yield the greatest success.

Salicylate- and quinine-induced tinnitus and effects of memantine.

CONCLUSION: Memantine, an antiglutamatergic drug, has been proposed as a treatment for tinnitus. OBJECTIVES: The purpose of this study was to determine if memantine would prevent salicylate-induced tinnitus. Local field potentials were also recorded from auditory cortex to determine what effect salicylate, memantine, and the combination of both drugs would have on evoked potential amplitudes. MATERIALS AND METHODS: Schedule induced polydipsia-avoidance conditioning was used to identify the doses of salicylate or quinine that reliably induced tinnitus in rats. Rats were trained to lick for water during quiet intervals and avoid licking during sound intervals. RESULTS: Rats injected with saline or a low dose of sodium salicylate or quinine failed to develop tinnitus-like behaviors. However, high doses of salicylate (150-300 mg/kg/day) or quinine (100-150 mg/kg/day) greatly reduced licks-in-quiet, behavior consistent with the presence of tinnitus. Licks-in-quiet increased slightly when memantine (1.5 or 3 mg/kg/day) was co-administered with salicylate; however, the effect was not statistically significant or dose-dependent. These results indicate that memantine does not completely suppress salicylate-induced tinnitus. Cortical auditory evoked potential amplitude increased after salicylate treatment; co-administration of memantine failed to block this salicylate-induced increase.

Comparison of benzodiazepines and the non-benzodiazepine agents zolpidem and zaleplon with respect to anxiolytic action as measured by increases in hypertonic NaCl-solution drinking in rats.

RATIONALE: In previous studies, water-deprived rats offered hypertonic 1.5% NaCl solutions to drink showed increased intakes when treated with agents known to have anxiolytic action in humans. This study explored two non-benzodiazepine (non-BZ) sedative-hypnotic agents, zolpidem and zaleplon, and compared them with three traditional BZs. OBJECTIVES: Although many studies confirm that treatment with BZs possessing sedative-hypnotic and anxiolytic actions also produces acute increases in food and fluid ingestion in animals, zolpidem has yielded conflicting results. To help resolve this question, we compared three BZs with zolpidem and zaleplon with respect to their actions in increasing the ingestion of 1.5% NaCl solution in water-deprived rats. METHODS: Rats were adapted to a water-deprivation schedule permitting drinking for 1 h daily. Once or twice each week, 1.5% NaCl solution was substituted for water during the drinking session and, 15 min pre-session, rats were given a drug or vehicle dose by gavage (p.o.) to delineate the dose-effect relationships for zolpidem, zaleplon, alprazolam, clonazepam, and chlordiazepoxide. Then, the dose-effect relationship for zolpidem was re-determined. A second study with two groups, using both zolpidem and clonazepam, explored whether following the dose-effect determination of a drug by a second determination affected the second relationship, and whether dose-effect determinations of either agent affected the results of the second agent investigated. RESULTS: All agents yielded dose-related increases in 1.5% NaCl solution ingestion, except the first zolpidem determination in the first study. In the second study, all determinations yielded dose-related increases, with no indication that the set of determinations for the first agent affected those for the second agent. CONCLUSIONS: The BZ and non-BZ agents explored yielded significant dose-effect relationships using this procedure, confirming their classification among the anxiolytic agents. The initial negative result for zolpidem in the first study may indicate a less reliable anxiolytic action for this agent, although this could not be resolved as attributable to drug history.

Pharmacokinetic determinants of cocaine's differential effects on locomotor and operant behavior.

Dose-response, effect-time and concentration-effect relations of intravenous cocaine (1-4 mg/kg) were investigated on contingency-controlled [fixed-ratio (FR) 70 performance] and unconditioned (locomotor activity) behaviors. Cocaine dose-response curves exhibited decreasing rates of response under the FR 70 schedule but increasing locomotor activity in a dose-related fashion. Effect-time profiles confirmed that these changes were time-dependent and provided additional clarity by mirroring the biexponential decay of cocaine concentrations with time. The duration of action of cocaine was comparatively shorter on locomotor activity than on FR performance. We integrated effect-time profiles of the two behaviors with concentration-time profiles simulated from our previously published pharmacokinetic parameters to derive cocaine's pharmacodynamic parameters. Classical inhibitory Emax and sigmoidal Emax models were used to describe cocaine's effects on FR performance and locomotor activity, respectively. Simultaneous pharmacokinetic-pharmacodynamic modeling reveals evidence of acute tolerance to cocaine in locomotor activity, as indicated by decreasing potency with dose, but not in contingency-controlled behavior.

Dose-dependent effects but not sensitization of DRL 45-s performance by oral d-amphetamine with cumulative- and repeated-dosing regimens.

The effects of d-amphetamine (AMPH) on a food-reinforced DRL 45-s schedule were evaluated using both cumulative- and repeated-dosing drug regimens. These two dosing regimens were designed to evaluate sensitization as a shift in the dose-response relationship, inasmuch as a range of doses was imposed within each dosing session. Daily 190-min sessions were composed of five 35-min subsessions separated by 3-min time-out periods. For selected sessions, five cumulative or repeated oral doses of AMPH were administered across the session, with a dose given during each of the time-out periods prior to the start of each subsession. Drug sessions were separated by intervals of 7-l0 days of non-drug sessions. Four cumulative dose-effect functions for AMPH were determined: for each dose-effect determination session, increasing doses (0.5, 1, 2, 4, 8 mg/kg gavage) were successively administered prior to each subsession. Four dose-effect functions were then determined in which a 0.5 mg/kg AMPH dose was repeated for each subsession (repetitive-dose regimen) rather than escalating subsession dose size. Then, four additional functions were determined using a larger repetitive dose of 1 mg/kg AMPH. Cumulative doses resulted in a leftward shift in the inter-response times (IRT) distribution accompanied by dose-dependent increases in subcriterion responses (< 45 s) and decreases in reinforced responses. The repeated doses of 0.5 or 1 mg/kg AMPH also resulted in progressive intrasession increases in subcriterion responses and decreases in reinforced responses. Although intrasession, accumulating dose effects were evident and statistically significant, there was no statistical significance or trend supporting sensitization of differential reinforcement of low-rate (DRL) responding with either cumulative- or repeated-dosing regimens across drugging sessions, unlike a previous, similar study in which oral cocaine resulted in robust sensitization.

Sensitization of operant behavior to oral cocaine with increasing- and repetitive-dose regimens.

This study evaluated whether operant behavior was subject to sensitization upon repeated exposure to cocaine. The behavior of eight rats was reinforced by food-pellet delivery under a differential reinforcement of low-rate (DRL) 45-s schedule, in daily sessions of 190 min. Each session was composed of five 35-min subsessions, with each subsession preceded by a 3-min time out period (TO). For selected sessions, a cumulative dose-effect relation for cocaine, using increasing doses, was first determined by oral gavage administration of a dose during each subsession. Three such cycles were given, separated by between seven and ten sessions. Later, four further cycles were given, using a repetitive 10 mg/kg cocaine per os (p.o.) dose, rather than an increasing dose. Under both dosing procedures, within a cocaine cycle (session), shorter (<45 s) inter-response times (IRT) progressively increased with doses, and reinforced responses decreased. As cycles were repeated, the shorter IRT increases became progressively more marked, indicating the development of sensitization to the effect of cocaine. With the second procedure (repetitive 10 mg/kg doses), reinforcement rate decreases became more marked as cycles were repeated, but this change did not occur using the increasing-dose procedure. Upon later exposure to repetitive 5 mg/kg dosing cycles, none of these rate changes occurred, and performances were equivalent to those occurring under saline cycles. Exposure to cumulative dose regimens of oral cocaine can result in the sensitization of operant behavior to the effects of cocaine.

Schedule-induced polydipsic consumption of hypertonic NaCl solutions: effects of chlordiazepoxide.

Rats were exposed to daily, 3-h sessions of schedule-induced polydipsia (SIP) in which either water, hypertonic NaCl solution (1.5% or 2.2%), or concurrent water and 1.5% NaCl were available. Each condition was in effect for several, consecutive weeks. Presession subcutaneous injections of chlordiazepoxide (CDZP) produced dose-related increases in the polydipsic ingestion of both NaCl solutions but had smaller and less certain effects on water consumption. Under the concurrent-fluid presentation condition, CDZP primarily increased NaCl solution consumption. Conditions generating SIP may function to attenuate what might be viewed as the punishing effects of ingesting highly hypertonic NaCl solutions, thereby permitting the chronic self-administration of large, daily amounts. Like many benzodiazepines, CDZP can attenuate the effects of punishment and thereby also increase NaCl solution ingestion. The two sources of punishment attenuation may be additive, with both differentially effecting greater increases in hypertonic NaCl ingestion, compared to water, when both fluids are presented concurrently.