title: The role of the subthalamic nucleus in L-DOPA induced dyskinesia in 6-hydroxydopamine lesioned rats.
abstract: L-DOPA is the most effective treatment for Parkinson's disease (PD), but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration. Our results show that chronic L-DOPA treatment does not modify the abnormal STN activity induced by the 6-hydroxydopamine lesion of the nigrostriatal pathway in this model. Likewise, we observed a loss of STN responsiveness to a single L-DOPA dose both in lesioned and sham animals that received daily L-DOPA treatment. We did not find any correlation between the abnormal involuntary movement (AIM) scores and the electrophysiological parameters of STN neurons recorded 24 h or 20-120 min after the last L-DOPA injection, except for the axial subscores. Nonetheless, unilateral chemical ablation of the STN with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia. In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner. Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB, phosphoDARPP-32, dopamine receptor (DR) D3 and DRD2/DRD1 ratio. The STN lesion attenuated the striatal molecular changes and normalized the DRD2/DRD1 ratio. Taken together, our results show that the STN plays a role, if modest, in the physiopathology of dyskinesias.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.
authors.forename: Asier
authors.initials: A
authors.lastname: Aristieta
authors.forename: Garikoitz
authors.initials: G
authors.lastname: Azkona
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Sagarduy
authors.forename: Cristina
authors.initials: C
authors.lastname: Miguelez
authors.forename: José Ángel
authors.initials: JÁ
authors.lastname: Ruiz-Ortega
authors.forename: Rosario
authors.initials: R
authors.lastname: Sanchez-Pernaute
authors.forename: Luisa
authors.initials: L
authors.lastname: Ugedo
mesh_terms: D000818:Animals; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D055724:Electrophysiological Phenomena; D007980:Levodopa; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016627:Oxidopamine; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D020531:Subthalamic Nucleus / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D007980:Levodopa; D016627:Oxidopamine