Letter abstract
Nature Medicine 14, 75 - 80 (2008)
Published online: 23 December 2007 | doi:10.1038/nm1693
Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor
Lane Bekar1,3, Witold Libionka1,3, Guo-Feng Tian1, Qiwu Xu1, Arnulfo Torres1, Xiaohai Wang1, Ditte Lovatt1, Erika Williams1, Takahiro Takano1, Jurgen Schnermann2, Robert Bakos1 & Maiken Nedergaard1
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.
- Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester, Rochester, New York 14642, USA.
- US National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 4D51, Bethesda, Maryland 20892, USA.
- These authors contributed equally to this work.
Correspondence to: Lane Bekar1,3 e-mail: lane_bekar@urmc.rochester.edu
Correspondence to: Maiken Nedergaard1 e-mail: nedergaard@urmc.rochester.edu
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