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.

Salicylate-induced peripheral auditory changes and tonotopic reorganization of auditory cortex.

The neuronal mechanism underlying the phantom auditory perception of tinnitus remains elusive at present. For over 25 years, temporary tinnitus following acute salicylate intoxication in rats has been used as a model to understand how a phantom sound can be generated. Behavioral studies have indicated that the pitch of salicylate-induced tinnitus in the rat is approximately 16 kHz. In order to better understand the origin of the tinnitus pitch measurements were made at the levels of auditory input and output; both cochlear and cortical physiological recordings were performed in ketamine/xylazine anesthetized rats. Both compound action potentials and distortion product otoacoustic emission measurements revealed a salicylate-induced band-pass-like cochlear deficit in which the reduction of cochlear input was least at 16 kHz and significantly greater at high and low frequencies. In a separate group of rats, frequency receptive fields of primary auditory cortex neurons were tracked using multichannel microelectrodes before and after systemic salicylate treatment. Tracking frequency receptive fields following salicylate revealed a population of neurons that shifted their frequency of maximum sensitivity (i.e. characteristic frequency) towards the tinnitus frequency region of the tonotopic axis (∼16 kHz). The data presented here supports the hypothesis that salicylate-induced tinnitus results from an expanded cortical representation of the tinnitus pitch determined by an altered profile of input from the cochlea. Moreover, the pliability of cortical frequency receptive fields during salicylate-induced tinnitus is likely due to salicylate's direct action on intracortical inhibitory networks. Such a disproportionate representation of middle frequencies in the auditory cortex following salicylate may result in a finer analysis of signals within this region which may pathologically enhance the functional importance of spurious neuronal activity concentrated at tinnitus frequencies.

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.