The Role of the Subthalamic Nucleus in L-DOPA Induced Dyskinesia in 6-Hydroxydopamine Lesioned Rats

14 p.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.This study was supported by grants from the Spanish Ministry of Science SAF 2009-08664 (LU), the department of Industry of the Basque Government S-PE10UN24 (LU and RSP) and Kutxa Obra social (RSP). AA and AS have a fellowship from the University of the Basque Country. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of manuscript

Sistema serotonergikoaren eta gongoil basalen arteko elkarrekintza: inplikazio funtzionala eta terapiaren alderdia Parkinsonen gaixotasunean

Serotonina neurotransmisoreak funtzio ezberdinak betetzen ditu informazio-prozesaketaren modulazioan hainbat familiatako hartzaileen aktibazioaren bidez. Hauen artean, erreten ionikoa den hartza ile bat (5-HT3) eta G proteinei lotutako (5-HT1, 5-HT2 , 5-HT4. 7) hartzaileak daude. Neurona serotonergiko gehienak mesentzefaloan kokatuta daude, rafe nukleoetan bereziki . Gongoil basaletara (GB) iristen diren proiekzioak , batez ere dorsal raphe nucleusetik (DRN) heltzen dira. GBak oso ondo antolatuta dauden nukleo subkot1ikalez eratutako sarea da, GB-etako nukleoak striatuma, subthalamic nucleusa (STN), globus pallidusa (barrukoa, GPi eta kanpokoa, GPe) eta substantia nigra (pars compacta, SNc, eta pars reticulata , SNr) direlarik. GBek kontrol motorrean , emozioan eta funtzio kognitiboan parte hartzen dute, eta oso garrantzitsuak dira Parkinsonen Gaixotasunean (PO). Berrikuspen honek serotoninak GBen modulazioan duen funtzioa laburbiltzen du. Bestalde , elkan·ekintza honek PGaren tratamenduan eta L-DOPArebn tratamendu kronikoak eragindako asaldu ra motorretan duen garrantzia eztabaidatzen da