title: 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 disorders. In addition, the use of DBS in a number of psychiatric diseases, including obsessive-compulsive disorders and depression, is currently being tested. 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 unknown. 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 tremor. 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.
authors.affiliation: Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester, Rochester, New York 14642, USA. lane_bekar@urmc.rochester.edu
authors.forename: Lane
authors.initials: L
authors.lastname: Bekar
authors.forename: Witold
authors.initials: W
authors.lastname: Libionka
authors.forename: Guo-Feng
authors.initials: GF
authors.lastname: Tian
authors.forename: Qiwu
authors.initials: Q
authors.lastname: Xu
authors.forename: Arnulfo
authors.initials: A
authors.lastname: Torres
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Wang
authors.forename: Ditte
authors.initials: D
authors.lastname: Lovatt
authors.forename: Erika
authors.initials: E
authors.lastname: Williams
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takano
authors.forename: Jurgen
authors.initials: J
authors.lastname: Schnermann
authors.forename: Robert
authors.initials: R
authors.lastname: Bakos
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D046690:Deep Brain Stimulation; D004594:Electrophysiology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism; D014202:Tremor / Q000378:metabolism / Q000628:therapy*
chemical_list: D043682:Receptor, Adenosine A1; D000255:Adenosine Triphosphate; D000241:Adenosine