Abstract
Subjective tinnitus is a chronic neurological disorder in which phantom sounds are perceived. Increasing evidence suggests that tinnitus is caused by neuronal hyperactivity in auditory brain regions, either due to a decrease in synaptic inhibition or an increase in synaptic excitation. One drug investigated for the treatment of tinnitus has been the uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, memantine, although the evidence relating to it has been unconvincing to date. We re-investigated the effects of memantine on the behavioral manifestations of tinnitus induced by acoustic trauma (a 16-kHz, 110-dB pure tone presented unilaterally for 1 h) in rats. We used a conditioned lick suppression model in which lick suppression was associated with the perception of high frequency sound resembling tinnitus and a suppression ratio (SR) was calculated by comparing the number of licks in the 15-s period preceding the stimulus presentation (A) and the 15-s period during the stimulus presentation (B), i.e., SR = B/(A + B). Acoustic trauma resulted in a significant increase in the auditory brainstem-evoked response (ABR) threshold in the affected ear (P ≤ 0.0001) and a decrease in the SR compared to sham controls in response to 32 kHz tones in five out of eight acoustic trauma-exposed animals. A 5-mg/kg dose of memantine significantly reduced the proportion of these animals which exhibited tinnitus-like behavior (2/5 compared to 5/5; P ≤ 0.006), suggesting that the drug reduced tinnitus. These results suggest that memantine may reduce tinnitus caused by acoustic trauma.
Highlights
Subjective tinnitus has been estimated to occur in 25.3% of people in the USA, with 7.9% experiencing it frequently (Shargorodsky et al, 2010)
Given the small amount of evidence relating to memantine in the context of tinnitus and the fact that the drug is currently approved for the treatment of moderate to severe Alzheimer’s disease (Olivares et al, 2012) and is available clinically, we considered it necessary to re-investigate the potential of memantine to treat tinnitus, using an acoustic trauma animal model in which tinnitus was indicated by a reduced suppression ratio (SR) in a conditioned lick suppression paradigm (Zheng et al, 2011a,b,c, 2012)
AUDITORY FUNCTION AND THE CONFIRMATION OF TINNITUS Unilateral acoustic trauma produced an immediate loss of auditory function in the exposed ear at 16 and 20 kHz as indicated by the elevated auditory brainstem-evoked response (ABR) thresholds [F (1, 167) = 16.52, P ≤ 0.0001 for group and F (1, 167) = 23.74 for the group × ear × time interaction, P ≤ 0.0001, i.e., the affected ear in the noise-exposed group showed a significant change in the ABR threshold between the pre- and post-exposure measurements; Figure 1]
Summary
Subjective tinnitus has been estimated to occur in 25.3% of people in the USA, with 7.9% experiencing it frequently (Shargorodsky et al, 2010). Data from animal and human studies have suggested that tinnitus is associated with neuronal hyperactivity at different levels of the central auditory pathways, including the dorsal cochlear nucleus, the inferior colliculus, auditory cortex, and the striatum (see Moller, 2000; Eggermont and Roberts, 2004; Eggermont, 2005; Kaltenbach, 2006; Roberts et al, 2010 for reviews; see Dong et al, 2010; Rauschecker et al, 2010; Middleton et al, 2011; Mulders and Robertson, 2011; Vogler et al, 2011; Leaver et al, 2011 for recent examples) For this reason, drugs that increase synaptic inhibition, such as benzodiazepines and GABAB receptor agonists, have been one avenue of investigation for potential new Abbreviations: SR, suppression ratio; ABR, auditory brainstem-evoked response; SPL, sound pressure level; BBN, broad band noise. Long-term tinnitus induced by acoustic trauma was prevented by locally applying another NMDA receptor, polyamine site, antagonist, ifenprodil, into the cochlea within the first 4 days after the acoustic trauma (Guitton and Dudai, 2007)
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