Alterations of auditory sensory gating in mice with noise-induced tinnitus treated with nicotine and cannabis extract

Abstract

AbstractAims/HypothesisTinnitus is a phantom sound perception affecting both auditory and limbic structures. The mechanisms of tinnitus remain unclear and it is debatable whether tinnitus alters attention to sound and the ability to inhibit repetitive sounds, a phenomenon also known as auditory gating. The objective of the study was to investigate whether noise-exposure interferes with auditory gating, and if nicotine or natural extracts of cannabis could improve auditory pre-attentional processing in noise-exposed mice.Methods22 male C57BL/6J mice were used in this study. Anesthetized mice were exposed to a 9-11 kHz narrow band noise (90 dBSPL for 1 hr) and sham exposed mice were used as controls. Hearing thresholds were measured using auditory brainstem responses (ABRs) and tinnitus was assessed using Gap prepulse inhibition of acoustic startle (GPIAS). After noise exposure to induce acute noise-induced tinnitus, mice were implanted with multi-electrodes to assess auditory event-related potentials (aERPs) in the dorsal hippocampus in response to paired clicks. Alterations of aERPs under nicotine (1.0 mg/kg, intraperitoneal (i.p.) or cannabis extract (100 mg/kg, i.p.) were evaluated (in isolation or in combination), the latter containing 47.25 mg/kg of tetrahydrocannabinol (THC); 0.43 mg/kg of cannabidiol (CBD) and 1.17 mg/kg of cannabinol (CBN), as analyzed by high-performance liquid chromatography (HPLC). Saline-treated animals were used as controls.ResultsOur results show that mice with behavioral evidence of tinnitus display auditory gating of repetitive click, but with larger amplitudes and longer latencies of the N40 component of the aERP waveform. In contrast, no difference was observed in the P80 amplitude and latency between groups or treatments. The combination of cannabis extract and nicotine also improved auditory gating ratio in mice with noise-induced tinnitus without permanent hearing threshold shifts by strongly increasing the first N40 click amplitude but without altering the second click response amplitude. Lastly, the longer latency of the N40 component appears due to an increased sensitivity to cannabis extract in noise-exposed mice compared to sham mice. This suggests that mice with acute noise-induced tinnitus have altered temporal processing of triggered attention when exposed to cannabis extract.Conclusion/InterpretationIn summary, we show that nicotine and cannabis extract alter sensory gating in mice with behavioral evidence of tinnitus and propose that the altered central plasticity in tinnitus is more sensitive to the combined actions on the cholinergic and the endocannabinoid systems. We conclude that the limbic system is involved in regulating sensory gating in both control sham mice and mice with acute noise-induced tinnitus, but that electrophysiological correlates of attention are altered by nicotine and cannabis extract to a higher degree in noise-exposed mice. These findings contribute to a better understanding of pharmacological modulation of auditory sensory gating.