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.

Loudness perception affected by early age hearing loss.

Tinnitus and hyperacusis, commonly seen in adults, are also reported in children. Although clinical studies found children with tinnitus and hyperacusis often suffered from recurrent otitis media, there is no direct study on how temporary hearing loss in the early age affects the sound loudness perception. In this study, sound loudness changes in rats affected by perforation of the tympanic membranes (TM) have been studied using an operant conditioning based behavioral task. We detected significant increases of sound loudness and susceptibility to audiogenic seizures (AGS) in rats with bilateral TM damage at postnatal 16 days. As increase to sound sensitivity is commonly seen in hyperacusis and tinnitus patients, these results suggest that early age hearing loss is a high risk factor to induce tinnitus and hyperacusis in children. In the TM damaged rats, we also detected a reduced expression of GABA receptor δ and α6 subunits in the inferior colliculus (IC) compared to the controls. Treatment of vigabatrin (60 mg/kg/day, 7-14 days), an anti-seizure drug that inhibits the catabolism of GABA, not only blocked AGS, but also significantly attenuated the loudness response. Administration of vigabatrin following the early age TM damage could even prevent rats from developing AGS. These results suggest that TM damage at an early age may cause a permanent reduction of GABA tonic inhibition which is critical towards the maintenance of normal loudness processing of the IC. Increasing GABA concentration during the critical period may alleviate the impairment in the brain induced by early age hearing loss.

Early age conductive hearing loss causes audiogenic seizure and hyperacusis behavior.

Recent clinical reports found a high incidence of recurrent otitis media in children suffering hyperacusis, a marked intolerance to an otherwise ordinary environmental sound. However, it is unclear whether the conductive hearing loss caused by otitis media in early age will affect sound tolerance later in life. Thus, we have tested the effects of tympanic membrane (TM) damage at an early age on sound perception development in rats. Two weeks after the TM perforation, more than 80% of the rats showed audiogenic seizure (AGS) when exposed to loud sound (120 dB SPL white noise, < 1 min). The susceptibility of AGS lasted at least sixteen weeks after the TM damage, even the hearing loss recovered. The TM damaged rats also showed significantly enhanced acoustic startle responses compared to the rats without TM damage. These results suggest that early age conductive hearing loss may cause an impaired sound tolerance during development. In addition, the AGS can be suppressed by the treatment of vigabatrin, acute injections (250 mg/kg) or oral intakes (60 mg/kg/day for 7 days), an antiepileptic drug that inhibits the catabolism of GABA. c-Fos staining showed a strong staining in the inferior colliculus (IC) in the TM damaged rats, not in the control rats, after exposed to loud sound, indicating a hyper-excitability in the IC during AGS. These results indicate that early age conductive hearing loss can impair sound tolerance by reducing GABA inhibition in the IC, which may be related to hyperacusis seen in children with otitis media.