Local NMDA Receptor Blockade Attenuates Chronic Tinnitus and Associated Brain Activity in an Animal Model

Abstract

Chronic tinnitus has no broadly effective treatment. Identification of specific markers for tinnitus should facilitate the development of effective therapeutics. Recently it was shown that glutamatergic blockade in the cerebellar paraflocculus, using an antagonist cocktail was successful in reducing chronic tinnitus. The present experiment examined the effect of selective N-methyl d-aspartate (NMDA) receptor blockade on tinnitus and associated spontaneous brain activity in a rat model. The NMDA antagonist, D(−)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.5 mM), was continuously infused for 2 weeks directly to the ipsilateral paraflocculus of rats with tinnitus induced months prior by unilateral noise exposure. Treated rats were compared to untreated normal controls without tinnitus, and to untreated positive controls with tinnitus. D-AP5 significantly decreased tinnitus within three days of beginning treatment, and continued to significantly reduce tinnitus throughout the course of treatment and for 23 days thereafter, at which time testing was halted. At the conclusion of psychophysical testing, neural activity was assessed using manganese enhanced magnetic resonance imaging (MEMRI). In agreement with previous research, untreated animals with chronic tinnitus showed significantly elevated bilateral activity in their paraflocculus and brainstem cochlear nuclei, but not in mid or forebrain structures. In contrast, D-AP5-treated-tinnitus animals showed significantly less bilateral parafloccular and dorsal cochlear nucleus activity, as well as significantly less contralateral ventral cochlear nucleus activity. It was concluded that NMDA-mediated glutamatergic transmission in the paraflocculus appears to be a necessary component of chronic noise-induced tinnitus in a rat model. Additionally, it was confirmed that in this model, elevated spontaneous activity in the cerebellar paraflocculus and auditory brainstem is associated with tinnitus.

Tinnitus and hyperacusis: Contributions of paraflocculus, reticular formation and stress

“…Functional imaging studies have also suggested that the PFL is involved in gating or modulating tinnitus (Brozoski et al, 2007; Chen et al, 2015). This interpretation was supported by behavioral studies showing that tinnitus was suppressed or enhanced by inactivating or activating the PFL (Bauer et al, 2013; Brozoski et al, 2007; Brozoski et al, 2013). Noise-induced spontaneous hyperactivity in the IC, considered a neural correlate of tinnitus, is enhanced by removal of the PFL whereas PFL removal had no effect on spontaneous activity in normal animals (Vogler et al, 2016).…”

“…In the case of chronic noise-induced tinnitus, manganese enhanced magnetic resonance imaging (MEMRI) revealed enhanced spontaneous activity in the PFL. Moreover, behavioral evidence of chronic noise-induced tinnitus was abolished by lesioning or inactivating the PFL (Bauer et al, 2013; Brozoski et al, 2007; Brozoski et al, 2013). Collectively, the imaging and behavioral results suggest that the PFL is involved in gating or modulating tinnitus and hyperacusis.…”

Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus

“…In the present study we examined whether non-competitive NMDA inhibition with round window applied AM-101 may be beneficial in counteracting the trauma-related deterioration of the IHC synapse and the maladaptive auditory patterns in the ascending auditory pathway during tinnitus [4,49]. It was already shown that the competitive NMDA receptor antagonist D-AP5 (D(-)-2-amino-5-phosphonopentanoic acid), when infused into non-auditory regions (paraflocculus) of rats months following noise exposure had a long-term relieving effect for tinnitus perception [50]. In case of synaptopathic tinnitus, the therapeutic time window of NMDA receptor inhibition not exactly known.…”

Id1/NR2B Receptor Pathway Regulates Rat Cochlear Sensory Epithelial Cell Survival after Radiation

“…Ifenprodil is a specific NMDA receptor antagonist that blocks NR2B receptor-mediated calcium currents and associated signal transduction pathways [Brozoski et al, 2013]. Ifenprodil (I2892, Sigma, MO, USA) was added to coculture medium at a concentration of 10 μM for 24 h prior to radiation exposure [Anastasio et al, 2009].…”