Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice
Background: Parkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The me...
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MDPI AG
2020-11-01
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| Series: | Brain Sciences |
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| Online Access: | https://www.mdpi.com/2076-3425/10/12/903 |
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| author | Ziqing Shi Ian J. Bamford Jonathan W. McKinley Suma Priya Sudarsana Devi Annie Vahedipour Nigel S. Bamford |
| author_facet | Ziqing Shi Ian J. Bamford Jonathan W. McKinley Suma Priya Sudarsana Devi Annie Vahedipour Nigel S. Bamford |
| author_sort | Ziqing Shi |
| collection | DOAJ |
| description | Background: Parkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The mechanism underlying LID remains unknown, and new treatments are needed. Experiments in mice have shown that DA deficiency promotes an imbalance between striatal acetylcholine (ACh) and DA that contributes to motor dysfunction. While treatment with L-Dopa improves DA availability, it promotes a paradoxical rise in striatal ACh and a further increase in the ACh to DA ratio may promote LID. Methods: We used conditional <i>Slc6a3<sup>DTR/+</sup></i> mice to model progressive DA deficiency and the β-adrenergic receptor (β-AR) antagonist propranolol to limit the activity of striatal cholinergic interneurons (ChIs). DA-deficient mice were treated with L-Dopa and the dopa decarboxylase inhibitor benserazide. LID and motor performance were assessed by rotarod, balance beam, and open field testing. Electrophysiological experiments characterized the effects of β-AR ligands on striatal ChIs. Results: LID was observed in a subset of DA-deficient mice. Treatment with propranolol relieved LID and motor hyperactivity. Electrophysiological experiments showed that β-ARs can effectively modulate ChI firing. Conclusions: The work suggests that pharmacological modulation of ChIs by β-ARs might provide a therapeutic option for managing LID. |
| first_indexed | 2024-03-10T14:36:11Z |
| format | Article |
| id | doaj.art-b1f71d16827e40968b79451b7aefede4 |
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| issn | 2076-3425 |
| language | English |
| last_indexed | 2024-03-10T14:36:11Z |
| publishDate | 2020-11-01 |
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| series | Brain Sciences |
| spelling | doaj.art-b1f71d16827e40968b79451b7aefede42023-11-20T22:10:24ZengMDPI AGBrain Sciences2076-34252020-11-01101290310.3390/brainsci10120903Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian MiceZiqing Shi0Ian J. Bamford1Jonathan W. McKinley2Suma Priya Sudarsana Devi3Annie Vahedipour4Nigel S. Bamford5Department of Pediatrics, Yale University, New Haven, CT 06510, USADepartment of Pediatrics, Yale University, New Haven, CT 06510, USADepartment of Pediatrics, Yale University, New Haven, CT 06510, USADepartment of Pediatrics, Yale University, New Haven, CT 06510, USADepartment of Pediatrics, Yale University, New Haven, CT 06510, USADepartment of Pediatrics, Yale University, New Haven, CT 06510, USABackground: Parkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The mechanism underlying LID remains unknown, and new treatments are needed. Experiments in mice have shown that DA deficiency promotes an imbalance between striatal acetylcholine (ACh) and DA that contributes to motor dysfunction. While treatment with L-Dopa improves DA availability, it promotes a paradoxical rise in striatal ACh and a further increase in the ACh to DA ratio may promote LID. Methods: We used conditional <i>Slc6a3<sup>DTR/+</sup></i> mice to model progressive DA deficiency and the β-adrenergic receptor (β-AR) antagonist propranolol to limit the activity of striatal cholinergic interneurons (ChIs). DA-deficient mice were treated with L-Dopa and the dopa decarboxylase inhibitor benserazide. LID and motor performance were assessed by rotarod, balance beam, and open field testing. Electrophysiological experiments characterized the effects of β-AR ligands on striatal ChIs. Results: LID was observed in a subset of DA-deficient mice. Treatment with propranolol relieved LID and motor hyperactivity. Electrophysiological experiments showed that β-ARs can effectively modulate ChI firing. Conclusions: The work suggests that pharmacological modulation of ChIs by β-ARs might provide a therapeutic option for managing LID.https://www.mdpi.com/2076-3425/10/12/903Parkinson’s diseasestriatumacetylcholinecholinergicinterneuronβ-adrenergic |
| spellingShingle | Ziqing Shi Ian J. Bamford Jonathan W. McKinley Suma Priya Sudarsana Devi Annie Vahedipour Nigel S. Bamford Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice Brain Sciences Parkinson’s disease striatum acetylcholine cholinergic interneuron β-adrenergic |
| title | Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice |
| title_full | Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice |
| title_fullStr | Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice |
| title_full_unstemmed | Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice |
| title_short | Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice |
| title_sort | propranolol relieves l dopa induced dyskinesia in parkinsonian mice |
| topic | Parkinson’s disease striatum acetylcholine cholinergic interneuron β-adrenergic |
| url | https://www.mdpi.com/2076-3425/10/12/903 |
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