Role of the Cholinergic System in Modulation of Tinnitus

Discussion in 'Research News' started by Lisa88, Nov 21, 2014.

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    1. Lisa88

      Lisa88 Member

      Tinnitus Since:
      Role of the Cholinergic System in Modulation of Tinnitus
      James Kaltenbach, Ph.D., Cleveland Clinic, Cleveland, OH

      Funding: $50,000

      Roadmap to a Cure: Pathway C

      Tinnitus is often attributed to hyperactivity of the brain’s auditory neurons. (Neurons are special cells that process sound information through electrical and chemical signals.) When a person is exposed to a loud sound or other tinnitus-inducing trauma, the brain circuits get altered and neurons start firing excessively. The result is the perception of sound when no external noise is present. In this model of tinnitus, the perception of sound (ringing) could be eliminated by reducing or compensating for the hyperactivity of these neurons.

      Dr. Kaltenbach’s laboratory at the Cleveland Clinic has been studying the brain’s cholinergic system—how neurons transmit information using chemical neurotransmitters—and has identified a specific neurotransmitter, acetylcholine, that modulates the hyperactivity that underlies tinnitus. His previous research has already shown that the chemical compound Carbachol successfully activates the acetylcholine receptor, reducing neural hyperactivity and effectively eliminating tinnitus. Unfortunately, this compound is not useful as a therapy due to its extreme side effects, which include significant damage to the heart and gastrointestinal system.

      However, Dr. Kaltenbach believes it is possible to identify a related compound that only targets neural activity related to tinnitus. (Each neuron has many receptor subtypes, each controlling a different neural reaction; the key to this study is finding a chemical compound that will stimulate only those receptors related to auditory activity.) Dr. Kaltenbach will use funding from ATA to explore three particularly promising compounds that target specific receptors in animals, to see which one best and most safely suppresses neuron hyperactivity and the perception of tinnitus. He is especially optimistic about work related to the muscarinic receptors, as there is already a strong consensus that drug interactions with these receptors are safe for humans.

      The potential impact of this research is huge. If Dr. Kaltenbach can show that activating one or more receptor subtypes results in suppression of tinnitus, it would implicate these specific neural areas as useful drug targets. If successful, this research would accelerate the development of commercially-available prescription medications to silence tinnitus.
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    2. Yowzerman

      Yowzerman Member

      Tinnitus Since:
      Would it be logical to think that taking an acetylcholine supplement might do some good here based on the mention in paragraph 2?
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    3. cdog

      cdog Member

      Tinnitus Since:
      Hmmm, this seems to go again Tzounopoulus's paper where he says :

      KCNQ channels, often KCNQ2 and KCNQ3, mediate the native neuronal M-type current (22, 32). M currents are strongly inhibited by activation of muscarinic acetylcholine receptors (mAChRs) and other G protein-coupled receptors that reduce membrane phosphatidylinositol-(4,5)-bisphosphate (PIP2) levels (4143). Given the important role of cholinergic activity in DCN synaptic plasticity (44) and that noise exposure increases cholinergic activity in the DCN (45, 46), our results suggest that noise-induced up-regulation of mAChR signaling may underlie the reduced KCNQ channel activity in tinnitus mice.​

      In other words according to this, the M currents of the Kv7+ channels (that Retigabine and similar drugs try to enhance) are actually inhibited (i.e. diminished) when acetylcholine receptors are activated. That is, their activation causes the problem, not the solution! What gives?

      @locoyeti @jazz
    4. locoyeti

      locoyeti Member Benefactor

      Tinnitus Since:
      that little blurb could have been mistakenly composed. i'd like to see his actual research.
    5. cdog

      cdog Member

      Tinnitus Since:
      Here's an article by him from 2013
      which seems to say the same thing :

      We hypothesized that since granule cells can be activated by cholinergic inputs, it might be possible to suppress tinnitus-related hyperactivity of fusiform cells using the cholinergic agonist, carbachol. To test this hypothesis, we recorded multiunit spontaneous activity in the fusiform soma layer (FSL) of the DCN in control and tone-exposed hamsters (10 kHz, 115 dB SPL, 4 h) before and after application of carbachol to the DCN surface. In both exposed and control animals, 100 µM carbachol had a transient excitatory effect on spontaneous activity followed by a rapid weakening of activity to near or below normal levels. In exposed animals, the weakening of activity was powerful enough to completely abolish the hyperactivity induced by intense sound exposure. This suppressive effect was partially reversed by application of atropine and was not associated with significant changes in neural best frequencies (BF) or BF thresholds. These findings demonstrate that noise-induced hyperactivity can be pharmacologically controlled and raise the possibility that attenuation of tinnitus may be achievable by using an agonist of the cholinergic system.
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    6. locoyeti

      locoyeti Member Benefactor

      Tinnitus Since:

      well thats weird. i guess one would start by checking the source references in the respective papers, and also how old the papers are, etc. if you could do the heavy lifting that would be great (this drug sort of makes such endeavors more difficult for me).
    7. rtwombly

      rtwombly Member

      Southeast USA
      Tinnitus Since:
      Cause of Tinnitus:
      @cdog Could Dr Tz be observing the "transient excitatory effect" and not the subsequent inhibition (of hyperactivity)? Could the inhibition be due to a MOA unrelated to opening of Kv channels?
    8. Viktor Salvatore

      Viktor Salvatore Member

      Las Vegas, Nevada
      Tinnitus Since:
      Hi all.
      I met Dr. Kaltenbach when i visited the Tinnitus Clinic held at the Cleveland Clinic. I also communicate with him regularly through email. When i found out from the ATA that his research was funded I dropped him an email thanking him for his research.

      On one occasion when i emailed Dr. Kaltenback, he offered to speak to me by phone as i was going through a tough time with the suffering. He was very genuine and had mentioned that he was working on several medicinal solutions to this menace. It did not surprise me when i found out he was given this research. I truly believe, Dr. Kaltenbach will soon have a medicine for us.

      Get it done Dc.

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    9. DebInAustralia

      DebInAustralia Member Benefactor Team Research

      Geelong, Victoria
      Tinnitus Since:
      thankyou for your post Viktor. that is very reassuring
    10. cdog

      cdog Member

      Tinnitus Since:
      From the first two paragraphs in the introduction section of the paper I quoted (, it seems the layout of what affects what is the following :

      1) Hyperactivity in the fusiform cells in the DCN cause tinnitus.
      2) Cartwheel cells exert a powerful inhibitory influence on fusiform cells
      3) 'Parallel fibers' (which are the axons of granule cells drive the cartwheel cells with excitatory inputs.
      4) Major source of input to the granule cells system that drives cartwheel cells is from olivocochlear bundle which is largely cholinergic.

      So we have : cholinergic (acetylcholine) influence on olivocochlear bundle -> causes granule cells to send excitatory inputs on their axons (the parallel fibers) to cartwheel cells -> causes cartwheel cells to exert an inhibitory influence on fusiform cells -> reduces hyperactivity in the fusiform cells and stops tinnitus.

      Now it could be that this cholinergic pathway (when acetylcholine is applied to olivococholear bundle), suppresses tinnitus, but some other cholinergic pathway (when acetylcholine is applied elsewhere, perhaps directly to fusiform cells) increases tinnitus (by inhibiting M channels, like the Tzounopoulis paper description).
    11. whale
      No Mood

      whale Member Benefactor

      Tinnitus Since:
      Cause of Tinnitus:
      Myofascial crap Bruxism, a jackhammer, stress who knows
      has there been any progress in this area?

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