Controlling Tremor with Adenosine

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Deep brain stimulation (DBS), in which high-frequency electrical stimuli are continuously delivered into the brain through implanted wires, is an effective treatment for movement disorders characterized by muscle tremors, including Parkinson’s disease and essential tremor (see Asaad and Eskandar). Bekar et al . provide evidence that one mechanism by which DBS reduces tremor is through stimulation of nonsynaptic release of adenosine triphosphate (ATP). Conversion of ATP to adenosine by ectoATPases then stimulates the activation of A1 receptors. The authors detected ATP in thalamic slices (and exposed mouse cortex) in response to high-frequency stimulation with a bioluminescence assay. Adenosine was detected in the thalamic slices with an amperometric biosensor, and production by ectoATPases was confirmed by pharmacological inhibition. The release of ATP was deemed to be nonsynaptic, because it did not require calcium and removal of extracellular calcium increased the accumulation of adenosine in response to high-frequency stimulation. The role of the A1 receptor and adenosine was also confirmed by showing that high-frequency stimulation failed to reduce evoked excitatory postsynaptic potentials (eEPSPs) in the presence of an A1 receptor antagonist or an inhibitor of ectoATPase activity. Application of adenosine or an A1 receptor agonist reduced eEPSP amplitude in the absence of high-frequency stimulation. In slices from mice deficient for A1 receptors, high-frequency stimulation failed to reduce eEPSP amplitude. Using a mouse model of essential tremor, the authors showed that administration of an A1 receptor antagonist exacerbated the tremor; delivery of adenosine or an A1 receptor agonist reduced the tremor, as did DBS. As DBS is also under investigation for application in other neurological disorders, such as obsessive-compulsive disorder and depression, understanding the mechanisms by which it exerts its effects may allow for more precise treatments that limit undesirable side effects. L. Bekar, W. Libionka, G.-F. Tian, Q. Xu, A. Torres, X. Wang, D. Lovatt, E. Williams, T. Takano, J. Schnermann, R. Bakos, M. Nedergaard, Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor. Nat. Med. 14 , 75-80 (2008). [PubMed] W. Asaad, E. Eskandar, The movers and shakers of deep brain stimulation. Nat. Med. 14 , 17-19 (2008). [PubMed]