Effects of kynurenic acid as a glutamate receptor antagonist in the guinea pig.

Glutamate excitotoxicity is implicated in both the genesis of neural injury and noise-induced hearing loss (NIHL). Acoustic overstimulation may result in excessive synaptic glutamate, resulting in excessive binding to post-synaptic receptors and the initiation of a destructive cascade of cellular events, thus leading to neuronal degeneration and NIHL. The purpose of this study was to determine whether this apparent excitotoxicity can be attenuated by kynurenic acid (KYNA), a broad-spectrum glutamate receptor antagonist, and protect against noise-induced temporary threshold shifts (TTS). Guinea pigs were randomly assigned to three separate groups. Base-line compound action potentials (CAP) thresholds and cochlear microphonics (CM) were recorded. Group I was treated with physiologic saline as a vehicle control applied to the round window membrane that was followed by 110 dB SPL wide-band noise for 90 min. Group II received 5 mM KYNA followed by noise exposure, and group III received 5 mM KYNA alone without noise exposure. Post-drug and noise levels of CAP thresholds and CM were then obtained. Noise exposure in the control group caused a significant temporary threshold shift (TTS) of 30-40 dB across the frequencies tested (from 3 kHz to 18 kHz). Animals that received 5 mM KYNA prior to noise exposure (group II) showed statistically significant protection against noise-induced damage and demonstrated a minimal TTS ranging between 5 and 10 dB at the same frequencies. Animals in group III receiving KYNA without noise exposure showed no change in thresholds. Additionally, cochlear microphonics showed no considerable difference in threshold shifts when controls were compared to KYNA-treated animals. These results show that antagonizing glutamate receptors can attenuate noise-induced TTS, suggesting that glutamate excitotoxicity may play a role in acoustic trauma.

Sarthran preserves cochlear microcirculation and reduces temporary threshold shifts after noise exposure.

The cause of noise-induced hearing loss remains unclear despite years of both epidemiologic and experimental investigation. Among the many possible pathophysiologic mechanisms that may contribute to noise-induced temporary or permanent threshold shifts are insufficiencies in cochlear blood flow. Although the literature is inconsistent, several histologic and physiologic studies demonstrate signs of reduced circulation in the cochlea after noise exposure. Recent studies using computer-enhanced intravital microscopy complement these earlier findings. Evidence suggests that these microcirculatory events are mediated in part by several circulating factors, including the potent vasoactive peptide angiotensin. This study investigated this possibility by pretreating with the angiotensin receptor antagonist sarthran during noise exposure and examining both cochlear microcirculation and auditory sensitivity. The results of these experiments show noise-induced ischemia in the lateral wall of the cochlea and temporary threshold shifts. Treatment with sarthran prevented this noise-induced microcirculatory ischemia and preserved auditory sensitivity at the low frequencies tested. These findings support a role for the angiotensinergic system during noise exposure and suggest that preservation of cochlear blood flow is functionally related to auditory sensitivity.

Noise level analysis of commercially available toys.

There have been several isolated reports of hearing loss due to noise levels from toys. Guidelines for noise production by toys is regulated by the Voluntary Product Standards PS 72-76: Toy Safety Act of 1969. To determine the current risk of noise induced hearing loss from toys currently on the market, 25 toys were purchased at a national toy store chain and sound levels were measured at distances approximating ear level (2.5 cm) and a child's arm length (25 cm) from the surface of the toy. Testing revealed peak sound levels ranging from 81 to 126 dBA at 2.5 cm and 80 to 115 dBA at 25 cm from the surface of the toy.

Alpha 1-adrenergic receptors in the mammalian cochlea.

The presence of alpha 1-adrenergic receptors in the mammalian cochlea has previously been suggested by physiological experiments using antagonists specific to the receptor. However, the characteristics of adrenergic receptors in the cochlea have not been described. By employing [3H]-prazosin, high affinity, specific binding sites with characteristics of alpha 1-adrenergic receptors have now been identified and characterized in the chinchilla cochlea. Analysis of the specific [3H]-prazosin binding indicates that prazosin binds to a single class of high-affinity sites with a dissociation constant, kd, of 2.9 x 10(-9) M and a maximum number of binding sites, Bmax, of 30 fmol/mg dry tissue. Furthermore, the binding characteristics suggest that these receptors may be related to the microvasculature of the cochlea. These results provide a rational basis for the observed actions of alpha-adrenergic drugs on the auditory system.

Pentoxifylline maintains cochlear microcirculation and attenuates temporary threshold shifts following acoustic overstimulation.

The etiology of noise-induced hearing loss is poorly understood despite years of clinical experience and experimental investigations. One potential mechanism which may contribute to noise-induced temporary threshold shifts (TTS) are vascular pathologies in the microcirculation of the cochlea. Several studies have demonstrated histologic evidence of reduced cochlear blood flow following noise exposure. Recent studies utilizing intravital microscopy (IVM) complement these histologic studies and furthermore demonstrate localized ischemia during noise exposure. The purpose of the current study was to attempt to maintain cochlear blood flow during noise exposure by treating with pentoxifylline, a xanthine derivative which promotes blood flow in capillary beds. The possibility that preserved cochlear microcirculation with pentoxifylline treatment attenuates noise-induced TTS was also examined in this study. The results show treatment with pentoxifylline maintains cochlear microcirculation as assessed by continuous red blood cell movement through capillaries. Pentoxifylline treatment did not prevent vasoconstriction or increased permeability often observed in the cochlear microvasculature during noise. Treatment with this drug reduced noise-induced TTS.

Alpha 1-adrenergic receptor antagonist blocks acute cocaine action on the compound action potential of the auditory nerve in the chinchilla.

Acute systemic cocaine injection is known to significantly decrease the compound action potential (CAP) amplitude of the auditory nerve. In an attempt to elucidate the mechanism underlying this phenomenon, the present study investigated the influence of prazosin, an adrenergic alpha 1-receptor antagonist, on the effect of cocaine on the CAP. Amplitude-intensity functions at 1 and 8 kHz were obtained before and after treatment with cocaine (experimental group) or saline (control group) in prazosin pretreated subjects. The characteristic reduction in CAP amplitude after an acute cocaine injection was blocked by 0.05 mg/kg prazosin. When subjects were re-injected with cocaine or saline one h after prazosin, the reduction in CAP amplitude following cocaine injection had recovered.

Effects of repeated cocaine injections on cochlear function.

The effects of repeated cocaine administration on cochlear function were evaluated by measuring amplitude-intensity and latency-intensity functions of the whole-nerve action potential of the auditory nerve. Whole-nerve action potential input/output functions obtained using tone-pips of 0.5, 1, 2, 4 and 8 kHz in a group of cocaine-treated subjects were compared with those obtained in saline-treated animals. All measurements were made 24 h after the last treatment. Amplitudes of whole-nerve action potentials were enhanced in the cocaine-treated animals compared to the control group. No statistically significant differences in latency-intensity functions were seen after cocaine treatment. The effect of chronic cocaine exposure also was examined on catecholamine innervation in the cochlea using immunohistochemical techniques. The density of adrenergic innervation was reduced in the cocaine-treated animals.

Lipid peroxidation inhibitor attenuates noise-induced temporary threshold shifts.

The purpose of this study was to investigate the protective effects of U74389F (Upjohn Co. Kalamazoo, MI), a 21-aminosteroid/lipid peroxidation inhibitor, and a member of the lazaroid drug class, on temporary threshold shifts in animals exposed to prolonged noise stimulation. Animals treated with U74389F and exposed to noise showed attenuated cochlear action potential threshold (CAP) shifts and cochlear microphonic (CM) when compared to non-drug treated noise-exposed subjects. These data suggest that inhibition of FOR induced lipid peroxidation is an important mechanism in noise-induced asymptotic temporary threshold shifts.

Relationships among psychoacoustic judgments, speech understanding ability and self-perceived handicap in tinnitus subjects.

Tinnitus is often a disturbing symptom which affects 6-20% of the population. Relationships among tinnitus pitch and loudness judgments, audiometric speech understanding measures and self-perceived handicap were evaluated in a sample of subjects with tinnitus and hearing loss (THL). Data obtained from the THL sample on the audiometric speech measures were compared to the performance of an age-matched hearing loss only (HL) group. Both groups had normal hearing through 1 kHz with a sloping configuration of < or = 20 dB/octave between 2-12 kHz. The THL subjects performed more poorly on the low predictability items of the Speech Perception in Noise Test, suggesting that tinnitus may interfere with the perception of speech signals having reduced linguistic redundancy. The THL subjects rated their tinnitus as annoying at relatively low sensation levels using the pitch-match frequency as the reference tone. Further, significant relationships were found between loudness judgment measures and self-rated annoyance. No predictable relationships were observed between the audiometric speech measures and perceived handicap using the Tinnitus Handicap Questionnaire. These findings support the use of self-report measures in tinnitus patients in that audiometric speech tests alone may be insufficient in describing an individual's reaction to his/her communication breakdowns.

The protective effects of allopurinol and superoxide dismutase on noise-induced cochlear damage.

Several studies have demonstrated that noise exposure may result in local vasoconstriction of cochlear vessels. The subsequent decrease in cochlear blood flow may lead to hypoxia and predispose to the formation of free oxygen radicals (FORs). If hypoxia occurs in response to noise exposure, then drugs that scavenge or block the formation of FORs should protect the cochlea from damage resulting from hypoxic or ischemic events as well as noise trauma. Rats were exposed to 60 hours of continuous broad-band noise (90 dB SPL) and treated with superoxide dismutase-polyethylene glycol (SOD-PEG), allopurinol, or a control vehicle. Exposure to noise resulted in significant threshold shifts at each frequency tested (3, 8, 12, and 18 kHz) as measured by tone burst-evoked compound action potentials and cochlear microphonics recorded from the round window. Both of these thresholds in drug-treated animals were attenuated compared with animals exposed to noise alone. These findings show that SOD-PEG and allopurinol may preserve cochlear sensitivity associated with noise exposure. This suggests that noise-induced damage to the cochlea may be related to the activity of FORs.

Acute effects of cocaine on cochlear function.

The effects of a single administration of cocaine on the cochlea was evaluated by measuring amplitude-intensity functions of the N1 response of the auditory nerve. Amplitude-intensity functions of the N1 response to tone-pips of 500 Hz, 1, 2, 4 and 8 kHz were obtained before and after intraperitoneal injection of either saline, 3 mg/kg or 25 mg/kg of cocaine. N1 amplitudes were decreased after the administration of cocaine and this reduction was found to be dose dependent. The influence of cocaine on cochlear blood flow (CBF) was examined in order to test the possibility that cocaine induced reductions in CBF underlie these electro-physiological changes. Corresponding decreases in cochlear blood flow after cocaine exposure were observed.

Response of auditory-nerve fibers to intensity increments in a multitone complex: neural correlates of profile analysis.

Recent psychophysical studies have shown that the detection of an intensity increment superimposed on the center component (1 kHz) of a multitone complex (1, 3, 7, or 11 components) improves as more components are added outside of the critical band. It has been suggested that this form of intensity discrimination is based on a change in the neural profile. To test this hypothesis, neural profiles were constructed by plotting the degree of phase locking to the 1-kHz tone as a function of each unit's characteristic frequency (CF). Neural phase-locking profile to the 1-component signal at 1 kHz had a broad peak; however, the neural profile became narrower as the number of components in the signal increased. The just detectable increment for the 1-component condition was -5 dB re: 1000-Hz component level (3.86-dB increment plus component level re: component level), whereas, for the 3-, 7-, and 11-component conditions, it was -15 dB re: component level (1.42 dB). The neural and psychophysical IDL for the chinchilla were similar for the 1-component condition. However, the overall trends in the psychophysical and neural data are different. In the psychophysical studies IDL is typically poorest in the 3-component condition and improves when more components are added. By contrast, the neural IDL was poorest in the 1-component condition and improved when more components were added. In the multicomponent conditions, units with CFs in 492-1380 Hz were found to be more sensitive in detecting the intensity increment to the 1000-Hz component.

Middle-ear response in the chinchilla and its relationship to mechanics at the base of the cochlea.

The responses of the malleus and the stapes to sinusoidal acoustic stimulation have been measured in the middle ears of anesthetized chinchillas using the Mössbauer technique. With "intact" bullas (i.e., closed except for venting via capillary tubing), the vibrations of the tip of the malleus reach a maximal peak velocity of about 2 mm/s in responses to 100-dB SPL tones in the frequency range 500-6000 Hz; vibration velocity diminishes toward lower frequencies with a slope of about 6 dB/oct. Opening the bulla widely increases the responses to low-frequency stimuli by as much as 16 dB. At low frequencies, malleus response sensitivity with either open or intact bullas far exceeds all previous measurements in cats and matches or exceeds such measurements in guinea pigs. Whether measured in open or intact bullas, phase-versus-frequency curves closely approximate those predicted from the magnitude-versus-frequency curves by minimum phase theory. The stapes responses are similar to those of the malleus, except that stapes response magnitude is lower, on the average, by 7.5 dB at frequencies below 2 kHz and 10.7 dB at 2 kHz and above. Comparison of the responses of the middle ear with those of the basilar membrane at a site 3.5 mm from the stapes indicates that, at frequencies below 150 Hz, the basilar membrane displacement is proportional to stapes acceleration. At frequencies between 150 and 2000 Hz, basilar membrane displacement is proportional to stapes velocity.

Auditory intensity discrimination in the chinchilla.

A positive reinforcement conditioning procedure was used to train chinchillas to respond to intensity differences between successively occurring tone bursts. Intensity difference limens were measured at 0.5, 1, 4, and 8 kHz at five intensities ranging from 10- to 55-dB sensation level. The intensity difference limen decreased from approximately 8 dB near threshold to approximately 3.5 dB at the highest level. The intensity difference limens for the chinchilla were considerably larger than those for humans as well as several other mammals; however, the results were similar to those obtained for the parakeet. The present results from intensity discrimination appeared to be related to previous data for the discrimination of amplitude modulated noise.