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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.

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Effect of subthalamic nucleus lesion on the severity of L-DOPA-induced dyskinesia.Evolution of (A) AIM scores/session, showing significant reduction after STN lesion in the sum of axial, limb and orolingual AIMs scored per session, whereas (B) locomotive AIMs scored per session were similar in both groups. The arrow marks the time of STN injection at day 22. Graphical representation of AIM scores/time point (AUC) comparing the day before STN injection (day 21st, black triangle) and the last testing session after STN injection (day 48th, black square). Time course of axial, limb and orolingual AIMs scored in (C) STN-lesion and (D) STN-sham animal groups. The results show a significant decrease in AIMs scores after STN lesion. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni post-hoc). * p<0.05 vs STN-sham (two-way RM ANOVA, followed by Bonferroni post-hoc). #p<0.05 (two-way RM ANOVA, followed by Bonferroni post-hoc).
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pone-0042652-g005: Effect of subthalamic nucleus lesion on the severity of L-DOPA-induced dyskinesia.Evolution of (A) AIM scores/session, showing significant reduction after STN lesion in the sum of axial, limb and orolingual AIMs scored per session, whereas (B) locomotive AIMs scored per session were similar in both groups. The arrow marks the time of STN injection at day 22. Graphical representation of AIM scores/time point (AUC) comparing the day before STN injection (day 21st, black triangle) and the last testing session after STN injection (day 48th, black square). Time course of axial, limb and orolingual AIMs scored in (C) STN-lesion and (D) STN-sham animal groups. The results show a significant decrease in AIMs scores after STN lesion. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni post-hoc). * p<0.05 vs STN-sham (two-way RM ANOVA, followed by Bonferroni post-hoc). #p<0.05 (two-way RM ANOVA, followed by Bonferroni post-hoc).

Mentions: In order to clarify the involvement of the STN in LID, a group of dyskinetic rats were injected with ibotenic acid (STN-lesion group) or vehicle (STN-sham group) into the STN ipsilateral to the 6-OHDA lesion. Five days later, AIM rating was continued for 6 additional sessions. Before the STN injection there were no differences in AIM scores between groups (Figure 5A). After the injection, animals in the STN-lesion group showed a reduction in the AIM scores compared to their pre-lesion scores (F(6,78) = 7.418, p<0.001; Figure 5A) while in the STN-sham group there were no changes between pre- and post-injection scores. Post injection scores were significantly different between the two groups (F(1,85) = 5.513, p<0.05; Figure 5A). On the other hand, locomotive AIM scores were not modified by the STN lesion (Figure 5B and data not shown).


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 on the severity of L-DOPA-induced dyskinesia.Evolution of (A) AIM scores/session, showing significant reduction after STN lesion in the sum of axial, limb and orolingual AIMs scored per session, whereas (B) locomotive AIMs scored per session were similar in both groups. The arrow marks the time of STN injection at day 22. Graphical representation of AIM scores/time point (AUC) comparing the day before STN injection (day 21st, black triangle) and the last testing session after STN injection (day 48th, black square). Time course of axial, limb and orolingual AIMs scored in (C) STN-lesion and (D) STN-sham animal groups. The results show a significant decrease in AIMs scores after STN lesion. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni post-hoc). * p<0.05 vs STN-sham (two-way RM ANOVA, followed by Bonferroni post-hoc). #p<0.05 (two-way RM ANOVA, followed by Bonferroni post-hoc).
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pone-0042652-g005: Effect of subthalamic nucleus lesion on the severity of L-DOPA-induced dyskinesia.Evolution of (A) AIM scores/session, showing significant reduction after STN lesion in the sum of axial, limb and orolingual AIMs scored per session, whereas (B) locomotive AIMs scored per session were similar in both groups. The arrow marks the time of STN injection at day 22. Graphical representation of AIM scores/time point (AUC) comparing the day before STN injection (day 21st, black triangle) and the last testing session after STN injection (day 48th, black square). Time course of axial, limb and orolingual AIMs scored in (C) STN-lesion and (D) STN-sham animal groups. The results show a significant decrease in AIMs scores after STN lesion. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni post-hoc). * p<0.05 vs STN-sham (two-way RM ANOVA, followed by Bonferroni post-hoc). #p<0.05 (two-way RM ANOVA, followed by Bonferroni post-hoc).
Mentions: In order to clarify the involvement of the STN in LID, a group of dyskinetic rats were injected with ibotenic acid (STN-lesion group) or vehicle (STN-sham group) into the STN ipsilateral to the 6-OHDA lesion. Five days later, AIM rating was continued for 6 additional sessions. Before the STN injection there were no differences in AIM scores between groups (Figure 5A). After the injection, animals in the STN-lesion group showed a reduction in the AIM scores compared to their pre-lesion scores (F(6,78) = 7.418, p<0.001; Figure 5A) while in the STN-sham group there were no changes between pre- and post-injection scores. Post injection scores were significantly different between the two groups (F(1,85) = 5.513, p<0.05; Figure 5A). On the other hand, locomotive AIM scores were not modified by the STN lesion (Figure 5B and data not shown).

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