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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 the different subtypes of L-DOPA-induced dyskinesia.Evolution of AIM scores/session of the (A) axial, (C) limb and (E) orolingual AIMs pre- and post-STN injection, comparing STN-lesion and STN-sham groups. Time course of score for each subtype of AIM pre- and post-STN injection; there were significant differences between pre- and post- injection in the STN-lesion in (B) axial, (D) limb and (F) oral subtypes. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). (G) The response to buspirone was maintained after the STN lesion, but the effect was significantly smaller than in the (H) STN-sham group. Groups: 6-OHDA L-DOPA+STN-lesion (n = 6) and 6-OHDA L-DOPA+STN-sham (n = 5). (I) Thionine-staining of the STN (upper panel). The bottom panels correspond to higher magnification of the ipsilateral (right) and contralateral (left) sides. Scale bar: 400 µm (upper panel) and 200 µm (lower panel). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni). * 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-g006: Effect of subthalamic nucleus lesion on the severity of the different subtypes of L-DOPA-induced dyskinesia.Evolution of AIM scores/session of the (A) axial, (C) limb and (E) orolingual AIMs pre- and post-STN injection, comparing STN-lesion and STN-sham groups. Time course of score for each subtype of AIM pre- and post-STN injection; there were significant differences between pre- and post- injection in the STN-lesion in (B) axial, (D) limb and (F) oral subtypes. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). (G) The response to buspirone was maintained after the STN lesion, but the effect was significantly smaller than in the (H) STN-sham group. Groups: 6-OHDA L-DOPA+STN-lesion (n = 6) and 6-OHDA L-DOPA+STN-sham (n = 5). (I) Thionine-staining of the STN (upper panel). The bottom panels correspond to higher magnification of the ipsilateral (right) and contralateral (left) sides. Scale bar: 400 µm (upper panel) and 200 µm (lower panel). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni). * 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: We analyzed separately the effect of the STN lesion on the scores for axial, limb and orolingual AIMs subtypes. After the STN lesion, the axial AIM scores were significantly reduced (F(6,78) = 6.481, p<0.001; Figure 6A) and significantly different from post-injection scores in the STN-sham group (F(1,85) = 8.508, p<0.01; Figure 6A). Additionally, the axial scores during the last testing session were also reduced after the lesion (F(1,286) = 15.95, p<0.001; Figure 6B). Limb AIM scores showed a similar profile and were significantly attenuated by the lesion (F(6,78) = 6.941, p<0.001; Figure 6C and F(1,286) = 7.986, p<0.01, Figure 6D). Likewise, orolingual AIM scores were significantly reduced (F(6,78) = 4.236, p<0.01; Figure 6E and F(1,286) = 10.25, p<0.01; Figure 6F). None of the AIMs subtypes was different after sham injection in the STN (data non 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 the different subtypes of L-DOPA-induced dyskinesia.Evolution of AIM scores/session of the (A) axial, (C) limb and (E) orolingual AIMs pre- and post-STN injection, comparing STN-lesion and STN-sham groups. Time course of score for each subtype of AIM pre- and post-STN injection; there were significant differences between pre- and post- injection in the STN-lesion in (B) axial, (D) limb and (F) oral subtypes. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). (G) The response to buspirone was maintained after the STN lesion, but the effect was significantly smaller than in the (H) STN-sham group. Groups: 6-OHDA L-DOPA+STN-lesion (n = 6) and 6-OHDA L-DOPA+STN-sham (n = 5). (I) Thionine-staining of the STN (upper panel). The bottom panels correspond to higher magnification of the ipsilateral (right) and contralateral (left) sides. Scale bar: 400 µm (upper panel) and 200 µm (lower panel). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni). * 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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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412805&req=5

pone-0042652-g006: Effect of subthalamic nucleus lesion on the severity of the different subtypes of L-DOPA-induced dyskinesia.Evolution of AIM scores/session of the (A) axial, (C) limb and (E) orolingual AIMs pre- and post-STN injection, comparing STN-lesion and STN-sham groups. Time course of score for each subtype of AIM pre- and post-STN injection; there were significant differences between pre- and post- injection in the STN-lesion in (B) axial, (D) limb and (F) oral subtypes. Groups: 6-OHDA L-DOPA+STN-lesion (n = 14) and 6-OHDA L-DOPA+STN-sham (n = 5). (G) The response to buspirone was maintained after the STN lesion, but the effect was significantly smaller than in the (H) STN-sham group. Groups: 6-OHDA L-DOPA+STN-lesion (n = 6) and 6-OHDA L-DOPA+STN-sham (n = 5). (I) Thionine-staining of the STN (upper panel). The bottom panels correspond to higher magnification of the ipsilateral (right) and contralateral (left) sides. Scale bar: 400 µm (upper panel) and 200 µm (lower panel). Data are expressed as mean ± S.E.M. &p<0.05 vs day 21st (one-way RM ANOVA, followed by Bonferroni). * 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: We analyzed separately the effect of the STN lesion on the scores for axial, limb and orolingual AIMs subtypes. After the STN lesion, the axial AIM scores were significantly reduced (F(6,78) = 6.481, p<0.001; Figure 6A) and significantly different from post-injection scores in the STN-sham group (F(1,85) = 8.508, p<0.01; Figure 6A). Additionally, the axial scores during the last testing session were also reduced after the lesion (F(1,286) = 15.95, p<0.001; Figure 6B). Limb AIM scores showed a similar profile and were significantly attenuated by the lesion (F(6,78) = 6.941, p<0.001; Figure 6C and F(1,286) = 7.986, p<0.01, Figure 6D). Likewise, orolingual AIM scores were significantly reduced (F(6,78) = 4.236, p<0.01; Figure 6E and F(1,286) = 10.25, p<0.01; Figure 6F). None of the AIMs subtypes was different after sham injection in the STN (data non 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