title: Early gene mapping after deep brain stimulation in a rat model of tardive dyskinesia: comparison with transient local inactivation.
abstract: Deep brain stimulation (DBS) has been extensively used in Parkinson's disease and is also currently being investigated in tardive dyskinesia (TD), a movement disorder induced by chronic treatment with antipsychotic drugs such as haloperidol (HAL). In rodents, vacuous chewing movements (VCMs) following chronic HAL administration are suggested to model orofacial dyskinesias in TD. We show that 60 min of DBS (100 μA, 90 μs, 130 Hz) applied to the entopeduncular (EPN) or subthalamic (STN) nuclei significantly decreases HAL-induced VCMs. Using zif268 as a neural activity marker, we found that in HAL-treated animals EPN stimulation increased zif268 mRNA levels in the globus pallidus (+65%) and substantia nigra compacta (+62%) and reticulata (+76%), while decreasing levels in the motor cortex and throughout the thalamus. In contrast, after STN DBS zif268 levels in HAL-treated animals decreased in all basal ganglia structures, thalamus and motor cortex (range: 29% in the ventrolateral caudate-putamen to 100% in the EPN). Local tissue inactivation by muscimol injections into the STN or EPN also reduced VCMs, but to a lesser degree than DBS. When applied to the EPN muscimol decreased zif268 levels in substantia nigra (-29%), whereas STN infusions did not result in significant zif268 changes in any brain area. These results confirm the effectiveness of DBS in reducing VCMs and suggest that tissue inactivation does not fully account for DBS effects in this preparation. The divergent effects of STN vs. EPN manipulations on HAL-induced zif268 changes suggest that similar behavioral outcomes of DBS in these two areas may involve different neuroanatomical mechanisms.
authors.affiliation: Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Meaghan C
authors.initials: MC
authors.lastname: Creed
authors.forename: Clement
authors.initials: C
authors.lastname: Hamani
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity; D046690:Deep Brain Stimulation / Q000379:methods*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D020392:Entopeduncular Nucleus / Q000502:physiology; D058785:GABA-A Receptor Agonists / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005917:Globus Pallidus / Q000502:physiology; D006220:Haloperidol / Q000633:toxicity; D008297:Male; D008409:Mastication / Q000187:drug effects; D009069:Movement Disorders / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D009118:Muscimol / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020531:Subthalamic Nucleus / Q000502:physiology; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D058785:GABA-A Receptor Agonists; D009118:Muscimol; D006220:Haloperidol