Effect of Cannabis extract on noise induced tinnitus and anxiety-related behaviour in adolescent mice

Abstract

Tinnitus is an auditory condition characterised as phantom sounds, often described as ringing or hissing sounds. Chronic bothersome tinnitus can lead to stress, anxiety and even depression, and still lacks standardized treatments. Recently Cannabis has gathered attention as it might modulate both behaviour and synaptic activity acting in the endocannabinoid system. However, literature is still inconclusive about beneficial or detrimental effects of Cannabis treatment for tinnitus. Here we used a model of noiseinduced tinnitus to investigate, first, if tinnitus is altered by a low dose Cannabis extract rich in tetrahydrocannabinol (extract, 2.44 mg/kg; THC, 1.0 mg/kg); second, if noiseexposure is related to increased anxiety and, third, if tinnitus-related anxiety is affected by Cannabis administration. We used gap prepulse inhibition of the acoustic startle (GPIAS) to assess tinnitus perception, and the open field (OF) and elevated plus maze (EPM), to evaluate anxiety behaviour. Our results show that only a subgroup of noiseexposed mice developed tinnitus-like behaviour (noise-exposed Tinnitus-like, and noiseexposed Not tinnitus-like) and that GPIAS index was not altered by Cannabis treatment in either group. When investigating anxiety-like behaviour we found noise-exposed mice to show reduced centre entries in the OF test 30 minutes after Cannabis extract administration compared to vehicle (p = 0.007) and reduced locomotion compared to sham (p = 0.042). In the EPM, noise-exposed mice entered fewer times into the closed arms compared to sham animals (p = 0.026). After Cannabis administration noiseexposed animals entered fewer times into the open arms of the EPM (p = 0.003). Subdivision of noise-exposed mice revealed, in the OF, that tinnitus-like mice entered less the centre after Cannabis administration compared to vehicle (p = 0.022). In the EPM, tinnitus-like and not tinnitus-like mice showed reduced entries in closed arms and open arms, respectively (tinnitus-like, p = 0.0167; not tinnitus-like, p = 0.033). Also, tinnitus-like mice spent more time in closed arms after Cannabis administration (p = 0.021). Thereby, specifically noise-exposed mice with tinnitus-like behaviour avoided the OF centre area and preferred to stay inside the closed arms of the EPM after cannabis administration. In summary this work shows that anxiety tests can be an addition to GPIAS tests to evaluate tinnitus and potential therapeutic substances. Future studies will test lower doses of cannabis extract for anxiolytic effects in treating tinnitus-related stress and anxiety.