Dopamine transporter is essential for the maintenance of spontaneous activity of auditory nerve neurones and their responsiveness to sound stimulation.
ABSTRACT Dopamine, a neurotransmitter released by the lateral olivocochlear efferents, has been shown tonically to inhibit the spontaneous and sound-evoked activity of auditory nerve fibres. This permanent inhibition probably requires the presence of an efficient transporter to remove dopamine from the synaptic cleft. Here, we report that the dopamine transporter is located in the lateral efferent fibres both below the inner hair cells and in the inner spiral bundle. Perilymphatic perfusion of the dopamine transporter inhibitors nomifensine and N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine into the cochlea reduced the spontaneous neural noise and the sound-evoked compound action potential of the auditory nerve in a dose-dependent manner, leading to both neural responses being completely abolished. We observed no significant change in cochlear responses generated by sensory hair cells (cochlear microphonic, summating potential, distortion products otoacoustic emissions) or in the endocochlear potential reflecting the functional state of the stria vascularis. This is consistent with a selective action of dopamine transporter inhibitors on auditory nerve activity. Capillary electrophoresis with laser-induced fluorescence (EC-LIF) measurements showed that nomifensine-induced inhibition of auditory nerve responses was due to increased extracellular dopamine levels in the cochlea. Altogether, these results show that the dopamine transporter is essential for maintaining the spontaneous activity of auditory nerve neurones and their responsiveness to sound stimulation.
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ABSTRACT: AIMS: In our aging society, age-related hearing loss (ARHL) or presbycusis is increasingly important. Here, we study the mechanism of ARHL using the senescence-accelerated mouse prone 8 (SAMP8) which is a useful model to probe the effects of aging on biological processes. RESULTS: We found that the SAMP8 strain displays premature hearing loss and cochlear degeneration recapitulating the processes observed in human presbycusis (i.e., strial, sensory, and neural degeneration). The molecular mechanisms associated with premature ARHL in SAMP8 mice involve oxidative stress, altered levels of antioxidant enzymes, and decreased activity of Complexes I, II, and IV, which in turn lead to chronic inflammation and triggering of apoptotic cell death pathways. In addition, spiral ganglion neurons (SGNs) also undergo autophagic stress and accumulated lipofuscin. INNOVATION AND CONCLUSION: Our results provide evidence that targeting oxidative stress, chronic inflammation, or apoptotic pathways may have therapeutic potential. Modulation of autophagy may be another strategy. The fact that autophagic stress and protein aggregation occurred specifically in SGNs also offers promising perspectives for the prevention of neural presbycusis.Antioxidants & Redox Signaling 09/2011; 16(3):263-74. · 8.20 Impact Factor
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ABSTRACT: Pharmacological studies suggest that dopamine release from lateral olivocochlear efferent neurons suppresses spontaneous and sound-evoked activity in cochlear nerve fibers and helps control noise-induced excitotoxicity; however, the literature on cochlear expression and localization of dopamine receptors is contradictory. To better characterize cochlear dopaminergic signaling, we studied receptor localization using immunohistochemistry or reverse transcriptase PCR and assessed histopathology, cochlear responses and olivocochlear function in mice with targeted deletion of each of the five receptor subtypes. In normal ears, D1, D2, and D5 receptors were detected in microdissected immature (postnatal days 10-13) spiral ganglion cells and outer hair cells but not inner hair cells. D4 was detected in spiral ganglion cells only. In whole cochlea samples from adults, transcripts for D1, D2, D4, and D5 were present, whereas D3 mRNA was never detected. D1 and D2 immunolabeling was localized to cochlear nerve fibers, near the first nodes of Ranvier (D2) and in the inner spiral bundle region (D1 and D2) where presynaptic olivocochlear terminals are found. No other receptor labeling was consistent. Cochlear function was normal in D3, D4, and D5 knock-outs. D1 and D2 knock-outs showed slight, but significant enhancement and suppression, respectively, of cochlear responses, both in the neural output [auditory brainstem response (ABR) wave 1] and in outer hair cell function [distortion product otoacoustic emissions (DPOAEs)]. Vulnerability to acoustic injury was significantly increased in D2, D4 and D5 lines: D1 could not be tested, and no differences were seen in D3 mutants, consistent with a lack of receptor expression. The increased vulnerability in D2 knock-outs was seen in DPOAEs, suggesting a role for dopamine in the outer hair cell area. In D4 and D5 knock-outs, the increased noise vulnerability was seen only in ABRs, consistent with a role for dopaminergic signaling in minimizing neural damage.Journal of Neuroscience 01/2012; 32(1):344-55. · 6.91 Impact Factor
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ABSTRACT: Abstract Conclusion: Our study demonstrates that the regulation of D2 receptors may be frequency specific. The reduction in cochlear microphonics (CM) and distortion product otoacoustic emission (DPOAE) amplitudes after perfusion with a D2 antagonist suggests that this receptor plays a role in the regulation of cochlear hair cell activation. Objectives: Dopaminergic terminals are subject to negative feedback from dopamine D2 receptors. In the present study we investigated whether the regulation of dopamine D2 receptor is frequency specific and evaluated changes in CM in guinea pig cochlea. Methods: A total of 30 male guinea pigs were randomly assigned to 3 groups and perfused with artificial perilymph (AP), AP containing ethanol (0.1%), or a D2 antagonist (L741626) for 2 h. In each group, compound action potentials (CAPs) evoked by a 1, 2, 4, 8, 16 or 24 kHz tone pip, CM evoked by 4 kHz tone bursts, and DPOAEs were measured before and 2 h after perilymphatic perfusion. Results: Perfusion with the D2 antagonist resulted in increased CAP thresholds compared with the other two groups at high frequencies (4, 8, 16, 24 kHz, p < 0.05); however, no significant increase was observed at low frequencies (1, 2 kHz, p > 0.05). There was a significant reduction in DPOAEs and CM amplitudes after the 2 h perfusion with the D2 antagonist. A CM input/output (I/O) function curve plotted with the stimulating level as input and the CM relative amplitude as output indicated obvious nonlinearity after the 2 h perfusion in all three groups.Acta oto-laryngologica 05/2014; · 0.98 Impact Factor