Abstract
Tinnitus, characterised by the perception of sound without an external acoustic stimulus, remains a challenging auditory disorder with poorly understood underlying mechanisms. Recent evidence suggests that dysregulation of dopaminergic pathways may contribute to the pathophysiology of tinnitus. However, little is known about dopaminergic neurotransmission in the auditory and limbic regions that are speculated to be involved in the generation and maintenance of chronic tinnitus. The present study investigated dopamine neurotransmission in auditory and limbic regions, specifically the nucleus accumbens (NAcc) shell and the primary auditory cortex, to elucidate its role in tinnitus perception.
We first examined whether electrical stimulation of the ventral tegmental area (VTA) could induce dopamine release in the primary auditory cortex of anaesthetised rats using fast-scan cyclic voltammetry. Comparisons were made with the NAcc shell, and selective inhibitors of dopamine and noradrenaline transporters were used to identify the recorded neurochemical signal.
VTA stimulation elicited low but measurable dopamine release in the primary auditory cortex (15.31 ± 4.59 nM). The NAcc shell exhibited significantly higher magnitude of phasic dopamine release, with approximately 6-fold higher Δ peak dopamine release and 2.2-fold higher Δ area under the curve compared to the primary auditory cortex. These results indicate that VTA stimulation elicits more rapid and pronounced phasic dopamine release in the NAcc shell relative to the primary auditory cortex, suggesting differential dopaminergic modulation of these regions.
We then assessed VTA-evoked dopamine transmission in the NAcc shell and primary auditory cortex in a tinnitus model. Tinnitus was induced by unilateral acoustic trauma and confirmed behaviourally using conditioned lick-suppression paradigm. Approximately 47% of noise-exposed animals developed tinnitus with sensory features similar to 20 kHz and/or 32 kHz tones. At baseline, phasic dopamine responses in the NAcc shell to VTA stimulation were significantly lower in the tinnitus and non-tinnitus groups compared to sham animals, but this difference was not observed in the primary auditory cortex. This suggests that a single acoustic trauma event can disrupt dopamine transmission in the NAcc shell 3–6 months later. Interestingly, dopamine clearance in the NAcc shell of non-tinnitus animals was significantly prolonged following dopamine transporter inhibition, suggesting a potential reduction in dopamine transporter density or basal functional activity within the NAcc shell of this group. This finding suggests a possible compensatory mechanism that may confer resilience against the development of tinnitus following acoustic trauma.
Immunohistochemistry revealed significantly reduced tyrosine hydroxylase immunoreactive fibres within the prelimbic and infralimbic cortices of the medial prefrontal cortex in tinnitus animals compared to non-tinnitus and sham groups. This reduction could potentially affect various functions associated with this region, such as sensory gating and prediction error processing, which have been implicated in chronic tinnitus.
Our findings demonstrate, for the first time, a complex pattern of changes across different aspects of dopamine neurotransmission in tinnitus and non-tinnitus animals following acoustic trauma. These findings provide new insights into the potential role of dopaminergic signalling in tinnitus and suggest avenues for future research and potential therapeutic interventions.