The role of the subthalamic nucleus in L-DOPA induced dyskinesia in 6-hydroxydopamine lesioned rats

• Published in: PloS one Vol. 7; no. 8; p. e42652
• Main Authors: Aristieta, Asier, Azkona, Garikoitz, Sagarduy, Ainhoa, Miguelez, Cristina, Ruiz-Ortega, José Ángel, Sanchez-Pernaute, Rosario, Ugedo, Luisa
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.08.2012; Public Library of Science (PLoS)
• Subjects: 6-Hydroxydopamine; Acids; Animals; Basal ganglia; Biology; Buspirone; Central nervous system diseases; Complications; Complications and side effects; Dentistry; Dihydroxyphenylalanine; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; Dopamine D3 receptors; Drug dosages; Dyskinesia; Dyskinesia, Drug-Induced - metabolism; Dyskinesia, Drug-Induced - pathology; Dyskinesia, Drug-Induced - physiopathology; Electrical stimuli; Electrophysiological Phenomena; Experiments; Ibotenic acid; Laboratory animals; Levodopa; Medical research; Medical treatment; Medicine; Movement disorders; Neostriatum; Neostriatum - metabolism; Neostriatum - pathology; Neostriatum - physiopathology; Neurodegenerative diseases; Neurons - metabolism; Neurons - pathology; Nuclei; Oxidopamine; Parkinson Disease - pathology; Parkinson Disease - physiopathology; Parkinson's disease; Pharmacology; Phenols (Class of compounds); Rats; Rats, Sprague-Dawley; Regression Analysis; Rodents; Solitary tract nucleus; Stem cells; Subthalamic nucleus; Subthalamic Nucleus - metabolism; Subthalamic Nucleus - physiopathology; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042652

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.