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Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor

Abstract

Deep brain stimulation (DBS) is a widely used neurosurgical approach to treating tremor and other movement disorders1,2,3. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested4,5,6. Despite the rapid increase in the number of individuals with surgically implanted stimulation electrodes, the cellular pathways involved in mediating the effects of DBS remain unknown1. Here we show that DBS is associated with a marked increase in the release of ATP, resulting in accumulation of its catabolic product, adenosine. Adenosine A1 receptor activation depresses excitatory transmission in the thalamus and reduces both tremor- and DBS-induced side effects. Intrathalamic infusion of A1 receptor agonists directly reduces tremor, whereas adenosine A1 receptor–null mice show involuntary movements and seizure at stimulation intensities below the therapeutic level. Furthermore, our data indicate that endogenous adenosine mechanisms are active in tremor, thus supporting the clinical notion that caffeine, a nonselective adenosine receptor antagonist, can trigger or exacerbate essential tremor7. Our findings suggest that nonsynaptic mechanisms involving the activation of A1 receptors suppress tremor activity and limit stimulation-induced side effects, thereby providing a new pharmacological target to replace or improve the efficacy of DBS.

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Figure 1: HFS triggers release of ATP and adenosine in thalamic slices.
Figure 2: A1 receptor activation reduces excitatory transmission after HFS.
Figure 3: HFS reduces tremor power.
Figure 4: Antitremor effect of HFS is mediated by A1 receptor activation.

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Acknowledgements

We thank S. Goldman and E. Vates for comments on the manuscript. This work was supported by the Mathers Charitable Foundation; National Institutes of Health grants NS30007, NS39559 and NS050315; the Adelson Program in Neural Repair and Regeneration; The Philip-Morris Organization; the New York State Spinal Cord Injury Research Board and the Canadian Institutes of Health Research.

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Correspondence to Lane Bekar or Maiken Nedergaard.

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Bekar, L., Libionka, W., Tian, GF. et al. Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor. Nat Med 14, 75–80 (2008). https://doi.org/10.1038/nm1693

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