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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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Electrophysiological characterization of the subthalamic nucleus.(A) Firing rate of STN glutamatergic neurons. Baseline firing rate (white bars) was significantly different between the groups (F(4,307) = 15.25, p<0.0001, one-way ANOVA). The acute L-DOPA challenge (grey bars), induced an increase in firing rate in sham saline animals only. (B) Coefficient of variation (%). Baseline activity recording (white bars) showed significant differences between groups (F(4,307) = 11.85, p<0.0001, one-way ANOVA) and acute L-DOPA treatment produced a significant reduction in the sham saline group. (C) Percentage of bursting, random and tonic neurons. Baseline burst firing pattern (white bars) was significantly increased in 6-OHDA lesioned groups (p<0.05, Fisher's test). Both sham groups showed a trend to increase the number of bursting neurons after an acute L-DOPA dose (sham saline, p = 0.08, and sham L-DOPA, p = 0.06 vs its baseline). Data are expressed as mean ± S.E.M. All data included in the acute L-DOPA challenge were obtained between 20 and 120 min after L-DOPA injection (time period corresponding to high dyskinetic behaviour). * p<0.05 vs sham saline and sham L-DOPA (one-way ANOVA, followed by Bonferroni post-hoc). &p<0.05 vs before L-DOPA administration (unpaired t test). #p<0.05 vs sham saline and sham L-DOPA (Fisher's exact test for firing pattern).
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pone-0042652-g004: Electrophysiological characterization of the subthalamic nucleus.(A) Firing rate of STN glutamatergic neurons. Baseline firing rate (white bars) was significantly different between the groups (F(4,307) = 15.25, p<0.0001, one-way ANOVA). The acute L-DOPA challenge (grey bars), induced an increase in firing rate in sham saline animals only. (B) Coefficient of variation (%). Baseline activity recording (white bars) showed significant differences between groups (F(4,307) = 11.85, p<0.0001, one-way ANOVA) and acute L-DOPA treatment produced a significant reduction in the sham saline group. (C) Percentage of bursting, random and tonic neurons. Baseline burst firing pattern (white bars) was significantly increased in 6-OHDA lesioned groups (p<0.05, Fisher's test). Both sham groups showed a trend to increase the number of bursting neurons after an acute L-DOPA dose (sham saline, p = 0.08, and sham L-DOPA, p = 0.06 vs its baseline). Data are expressed as mean ± S.E.M. All data included in the acute L-DOPA challenge were obtained between 20 and 120 min after L-DOPA injection (time period corresponding to high dyskinetic behaviour). * p<0.05 vs sham saline and sham L-DOPA (one-way ANOVA, followed by Bonferroni post-hoc). &p<0.05 vs before L-DOPA administration (unpaired t test). #p<0.05 vs sham saline and sham L-DOPA (Fisher's exact test for firing pattern).

Mentions: To investigate the effect of L-DOPA chronic treatment on the STN activity, neurons from sham and 6-OHDA lesioned rats treated with saline or L-DOPA were recorded 24 h after the last saline or L-DOPA dose (baseline). All cells recorded showed a biphasic action potential waveform with a duration of 1.0–1.5 ms (Figure 3A), were localized within the STN (Figure 3B) and displayed the characteristic firing patterns of STN neurons (Figure 3C, 3D and 3E). A total of 309 glutamatergic neurons were recorded in the STN: 51 neurons from sham saline group, 55 neurons from sham L-DOPA group, 60 neurons from 6-OHDA saline group and, 143 neurons from 6-OHDA L-DOPA group (Figure 4). We found significant differences between the sham and the 6-OHDA lesioned groups in the baseline firing rate (Figure 4A), regularity (Figure 4B), and pattern (Figure 4C), consistent with hyperactive STN features typical of DA denervated states. The mean firing rate was higher in the 6-OHDA saline animals compared with the sham saline group (12.26±0.64 Hz vs 8.18±0.49 Hz, p<0.05), and in the 6-OHDA L-DOPA group compared with sham L-DOPA (13.09±0.53 Hz vs 8.97±0.52 Hz, p<0.05). In the 6-OHDA saline group the firing activity was more irregular (the variation coefficient was 86.88±4.88% vs 62.33±4.20%, p<0.05) and the bursting activity was higher (51.22% vs 18.43%, p<0.05) and the amount of neurons showing a tonic (44.76% vs 76.72%) pattern was lower than that found in neurons recorded from the sham saline group, while the number of neurons showing a random (4.02% vs 4.85%) pattern in both groups was not different. Comparison between electrophysiological parameters obtained from 6-OHDA saline and 6-OHDA L-DOPA groups did not reveal any difference indicating that chronic treatment with L-DOPA did not modify the STN hyperactivity induced by 6-OHDA lesion.


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)

Electrophysiological characterization of the subthalamic nucleus.(A) Firing rate of STN glutamatergic neurons. Baseline firing rate (white bars) was significantly different between the groups (F(4,307) = 15.25, p<0.0001, one-way ANOVA). The acute L-DOPA challenge (grey bars), induced an increase in firing rate in sham saline animals only. (B) Coefficient of variation (%). Baseline activity recording (white bars) showed significant differences between groups (F(4,307) = 11.85, p<0.0001, one-way ANOVA) and acute L-DOPA treatment produced a significant reduction in the sham saline group. (C) Percentage of bursting, random and tonic neurons. Baseline burst firing pattern (white bars) was significantly increased in 6-OHDA lesioned groups (p<0.05, Fisher's test). Both sham groups showed a trend to increase the number of bursting neurons after an acute L-DOPA dose (sham saline, p = 0.08, and sham L-DOPA, p = 0.06 vs its baseline). Data are expressed as mean ± S.E.M. All data included in the acute L-DOPA challenge were obtained between 20 and 120 min after L-DOPA injection (time period corresponding to high dyskinetic behaviour). * p<0.05 vs sham saline and sham L-DOPA (one-way ANOVA, followed by Bonferroni post-hoc). &p<0.05 vs before L-DOPA administration (unpaired t test). #p<0.05 vs sham saline and sham L-DOPA (Fisher's exact test for firing pattern).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412805&req=5

pone-0042652-g004: Electrophysiological characterization of the subthalamic nucleus.(A) Firing rate of STN glutamatergic neurons. Baseline firing rate (white bars) was significantly different between the groups (F(4,307) = 15.25, p<0.0001, one-way ANOVA). The acute L-DOPA challenge (grey bars), induced an increase in firing rate in sham saline animals only. (B) Coefficient of variation (%). Baseline activity recording (white bars) showed significant differences between groups (F(4,307) = 11.85, p<0.0001, one-way ANOVA) and acute L-DOPA treatment produced a significant reduction in the sham saline group. (C) Percentage of bursting, random and tonic neurons. Baseline burst firing pattern (white bars) was significantly increased in 6-OHDA lesioned groups (p<0.05, Fisher's test). Both sham groups showed a trend to increase the number of bursting neurons after an acute L-DOPA dose (sham saline, p = 0.08, and sham L-DOPA, p = 0.06 vs its baseline). Data are expressed as mean ± S.E.M. All data included in the acute L-DOPA challenge were obtained between 20 and 120 min after L-DOPA injection (time period corresponding to high dyskinetic behaviour). * p<0.05 vs sham saline and sham L-DOPA (one-way ANOVA, followed by Bonferroni post-hoc). &p<0.05 vs before L-DOPA administration (unpaired t test). #p<0.05 vs sham saline and sham L-DOPA (Fisher's exact test for firing pattern).
Mentions: To investigate the effect of L-DOPA chronic treatment on the STN activity, neurons from sham and 6-OHDA lesioned rats treated with saline or L-DOPA were recorded 24 h after the last saline or L-DOPA dose (baseline). All cells recorded showed a biphasic action potential waveform with a duration of 1.0–1.5 ms (Figure 3A), were localized within the STN (Figure 3B) and displayed the characteristic firing patterns of STN neurons (Figure 3C, 3D and 3E). A total of 309 glutamatergic neurons were recorded in the STN: 51 neurons from sham saline group, 55 neurons from sham L-DOPA group, 60 neurons from 6-OHDA saline group and, 143 neurons from 6-OHDA L-DOPA group (Figure 4). We found significant differences between the sham and the 6-OHDA lesioned groups in the baseline firing rate (Figure 4A), regularity (Figure 4B), and pattern (Figure 4C), consistent with hyperactive STN features typical of DA denervated states. The mean firing rate was higher in the 6-OHDA saline animals compared with the sham saline group (12.26±0.64 Hz vs 8.18±0.49 Hz, p<0.05), and in the 6-OHDA L-DOPA group compared with sham L-DOPA (13.09±0.53 Hz vs 8.97±0.52 Hz, p<0.05). In the 6-OHDA saline group the firing activity was more irregular (the variation coefficient was 86.88±4.88% vs 62.33±4.20%, p<0.05) and the bursting activity was higher (51.22% vs 18.43%, p<0.05) and the amount of neurons showing a tonic (44.76% vs 76.72%) pattern was lower than that found in neurons recorded from the sham saline group, while the number of neurons showing a random (4.02% vs 4.85%) pattern in both groups was not different. Comparison between electrophysiological parameters obtained from 6-OHDA saline and 6-OHDA L-DOPA groups did not reveal any difference indicating that chronic treatment with L-DOPA did not modify the STN hyperactivity induced by 6-OHDA lesion.

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