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

Aristieta A, Azkona G, Sagarduy A, Miguelez C, Ruiz-Ortega JÁ, Sanchez-Pernaute R, Ugedo L - PLoS ONE (2012)

Bottom Line: 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.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.In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.

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.

Show MeSH

Related in: MedlinePlus

Effect of subthalamic nucleus lesion in protein expression in the striatum.(A) Western blot representative images (upper panel) and quantification (lower panel) of cFos protein showing no significant differences between the groups. (B) Quantification of ΔFosB/FosB western blot showed significant increased in 6-OHDA L-DOPA group versus 6-OHDA saline group ratio, indicating that L-DOPA treatment increase ΔFosB expression in the lesioned striatum. (C) pDARPP32/DARPP ratio was significantly higher in lesioned animal treated chronically with L-DOPA. (D)Results of the analysis of DRD1 and (E) DRD2 expression showing no significant differences between the groups. (F) Analysis of DRD2/DRD1 ratio showed a significant increase in 6-OHDA L-DOPA group. (G) DRD3 was significantly higher in 6-OHDA treated with L-DOPA compared to the animals that received saline. (H) mGluR5 protein expression quantification revealed a significant reduction in 6-OHDA L-DOPA group versus 6-OHDA saline group. Groups: sham L-DOPA (n = 7), 6-OHDA saline (n = 9), 6-OHDA L-DOPA (n = 10) and 6-OHDA L-DOPA+STN-lesion (n = 8). R = right, ipsilateral to sham or 6-OHDA injection; L = left, contralateral to sham or 6-OHDA injection. Data are expressed as mean ± S.E.M. * p<0.05 and ** p<0.01 (one-way ANOVA, followed by Bonferroni post-hoc).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3412805&req=5

pone-0042652-g007: Effect of subthalamic nucleus lesion in protein expression in the striatum.(A) Western blot representative images (upper panel) and quantification (lower panel) of cFos protein showing no significant differences between the groups. (B) Quantification of ΔFosB/FosB western blot showed significant increased in 6-OHDA L-DOPA group versus 6-OHDA saline group ratio, indicating that L-DOPA treatment increase ΔFosB expression in the lesioned striatum. (C) pDARPP32/DARPP ratio was significantly higher in lesioned animal treated chronically with L-DOPA. (D)Results of the analysis of DRD1 and (E) DRD2 expression showing no significant differences between the groups. (F) Analysis of DRD2/DRD1 ratio showed a significant increase in 6-OHDA L-DOPA group. (G) DRD3 was significantly higher in 6-OHDA treated with L-DOPA compared to the animals that received saline. (H) mGluR5 protein expression quantification revealed a significant reduction in 6-OHDA L-DOPA group versus 6-OHDA saline group. Groups: sham L-DOPA (n = 7), 6-OHDA saline (n = 9), 6-OHDA L-DOPA (n = 10) and 6-OHDA L-DOPA+STN-lesion (n = 8). R = right, ipsilateral to sham or 6-OHDA injection; L = left, contralateral to sham or 6-OHDA injection. Data are expressed as mean ± S.E.M. * p<0.05 and ** p<0.01 (one-way ANOVA, followed by Bonferroni post-hoc).

Mentions: First, we examined the expression of cFos protein that belongs to the immediate early gene family of transcription factors. Analysis of the western blots did not show significant differences in the expression of this indirect marker of neuronal activity (Figure 7A). We then analyzed the expression of ΔFosB, a stable truncated splice variant of FosB that has been associated with L-DOPA induced dyskinesia [38]. ΔFosB/FosB ratio was significantly different between the groups (F(3,30) = 4.884, p<0.01) and the post hoc analysis showed that the ratio was significantly higher in L-DOPA treated animals in comparison with saline treated animals (1.39±0.11 vs 0.96±0.006; Figure 7B). Levels in the STN-lesion group fell in between (1.16±0.14) and were not significantly different from either saline or L-DOPA groups.


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

Aristieta A, Azkona G, Sagarduy A, Miguelez C, Ruiz-Ortega JÁ, Sanchez-Pernaute R, Ugedo L - PLoS ONE (2012)

Effect of subthalamic nucleus lesion in protein expression in the striatum.(A) Western blot representative images (upper panel) and quantification (lower panel) of cFos protein showing no significant differences between the groups. (B) Quantification of ΔFosB/FosB western blot showed significant increased in 6-OHDA L-DOPA group versus 6-OHDA saline group ratio, indicating that L-DOPA treatment increase ΔFosB expression in the lesioned striatum. (C) pDARPP32/DARPP ratio was significantly higher in lesioned animal treated chronically with L-DOPA. (D)Results of the analysis of DRD1 and (E) DRD2 expression showing no significant differences between the groups. (F) Analysis of DRD2/DRD1 ratio showed a significant increase in 6-OHDA L-DOPA group. (G) DRD3 was significantly higher in 6-OHDA treated with L-DOPA compared to the animals that received saline. (H) mGluR5 protein expression quantification revealed a significant reduction in 6-OHDA L-DOPA group versus 6-OHDA saline group. Groups: sham L-DOPA (n = 7), 6-OHDA saline (n = 9), 6-OHDA L-DOPA (n = 10) and 6-OHDA L-DOPA+STN-lesion (n = 8). R = right, ipsilateral to sham or 6-OHDA injection; L = left, contralateral to sham or 6-OHDA injection. Data are expressed as mean ± S.E.M. * p<0.05 and ** p<0.01 (one-way ANOVA, followed by Bonferroni post-hoc).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412805&req=5

pone-0042652-g007: Effect of subthalamic nucleus lesion in protein expression in the striatum.(A) Western blot representative images (upper panel) and quantification (lower panel) of cFos protein showing no significant differences between the groups. (B) Quantification of ΔFosB/FosB western blot showed significant increased in 6-OHDA L-DOPA group versus 6-OHDA saline group ratio, indicating that L-DOPA treatment increase ΔFosB expression in the lesioned striatum. (C) pDARPP32/DARPP ratio was significantly higher in lesioned animal treated chronically with L-DOPA. (D)Results of the analysis of DRD1 and (E) DRD2 expression showing no significant differences between the groups. (F) Analysis of DRD2/DRD1 ratio showed a significant increase in 6-OHDA L-DOPA group. (G) DRD3 was significantly higher in 6-OHDA treated with L-DOPA compared to the animals that received saline. (H) mGluR5 protein expression quantification revealed a significant reduction in 6-OHDA L-DOPA group versus 6-OHDA saline group. Groups: sham L-DOPA (n = 7), 6-OHDA saline (n = 9), 6-OHDA L-DOPA (n = 10) and 6-OHDA L-DOPA+STN-lesion (n = 8). R = right, ipsilateral to sham or 6-OHDA injection; L = left, contralateral to sham or 6-OHDA injection. Data are expressed as mean ± S.E.M. * p<0.05 and ** p<0.01 (one-way ANOVA, followed by Bonferroni post-hoc).
Mentions: First, we examined the expression of cFos protein that belongs to the immediate early gene family of transcription factors. Analysis of the western blots did not show significant differences in the expression of this indirect marker of neuronal activity (Figure 7A). We then analyzed the expression of ΔFosB, a stable truncated splice variant of FosB that has been associated with L-DOPA induced dyskinesia [38]. ΔFosB/FosB ratio was significantly different between the groups (F(3,30) = 4.884, p<0.01) and the post hoc analysis showed that the ratio was significantly higher in L-DOPA treated animals in comparison with saline treated animals (1.39±0.11 vs 0.96±0.006; Figure 7B). Levels in the STN-lesion group fell in between (1.16±0.14) and were not significantly different from either saline or L-DOPA groups.

Bottom Line: 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.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.In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.

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.

Show MeSH
Related in: MedlinePlus