GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming
Levo-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease; however, most patients develop uncontrollable abnormal involuntary movements known as L-DOPA-induced dyskinesia. L-DOPA-induced dyskinesia can be reduced by pallidotomy of the medial globus pallidus or...
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| Language: | English |
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Elsevier
2020-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996120302540 |
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| author | Haruo Nishijima Fumiaki Mori Akira Arai Gang Zhu Koichi Wakabayashi Motohiro Okada Shinya Ueno Noritaka Ichinohe Chieko Suzuki Tomoya Kon Masahiko Tomiyama |
| author_facet | Haruo Nishijima Fumiaki Mori Akira Arai Gang Zhu Koichi Wakabayashi Motohiro Okada Shinya Ueno Noritaka Ichinohe Chieko Suzuki Tomoya Kon Masahiko Tomiyama |
| author_sort | Haruo Nishijima |
| collection | DOAJ |
| description | Levo-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease; however, most patients develop uncontrollable abnormal involuntary movements known as L-DOPA-induced dyskinesia. L-DOPA-induced dyskinesia can be reduced by pallidotomy of the medial globus pallidus or pallidal deep brain stimulation, suggesting that the medial globus pallidus plays a significant role in the development of L-DOPA-induced dyskinesia. In the present study, the pathological changes of the medial globus pallidus in L-DOPA-induced dyskinesia were studied in rat models of Parkinson's disease (unilateral 6-hydroxydopamine lesioning) and L-DOPA-induced dyskinesia (L-DOPA injection in Parkinson's disease-model rats twice daily for 2 weeks, confirmed by display of dyskinesia-like abnormal involuntary movements). L-DOPA-induced dyskinesia-model rats displayed medial globus pallidus hypertrophy, enlarged axon terminals surrounding the dendrites of medial globus pallidus neurons, and increased density of synaptic vesicles in enlarged axon terminals on the lesioned side. Synaptic terminal enlargement reversed after discontinuation of L-DOPA. Histological studies revealed the enlarged synaptic terminals were those of GABAergic striatal (direct pathway) neurons. A single injection of L-DOPA enhanced GABA release in the medial globus pallidus on the lesioned side in L-DOPA-induced dyskinesia-model rats compared to Parkinson's disease-model rats. In addition, microinjection of muscimol, a GABAA receptor agonist, into the medial globus pallidus on the lesioned side of Parkinson's disease-model rats induced dyskinesia-like abnormal involuntary movements. Microinjection of bicuculline, a GABAA receptor antagonist, into the medial globus pallidus on the lesioned side alleviated L-DOPA-induced dyskinesia in Parkinson's disease-model rats that had received L-DOPA prior to the microinjection. These results indicate that priming for L-DOPA-induced dyskinesia comprises excessive GABA storage in axon terminals of the direct pathway and that expression of L-DOPA-induced dyskinesia is associated with enhanced GABA release into the medial globus pallidus after L-DOPA dosing and the resultant excessive stimulation of GABAA receptors. |
| first_indexed | 2024-12-17T21:25:36Z |
| format | Article |
| id | doaj.art-00325d2a238a40c68eeeadc965d452f8 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T21:25:36Z |
| publishDate | 2020-09-01 |
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| series | Neurobiology of Disease |
| spelling | doaj.art-00325d2a238a40c68eeeadc965d452f82022-12-21T21:32:02ZengElsevierNeurobiology of Disease1095-953X2020-09-01143104979GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia primingHaruo Nishijima0Fumiaki Mori1Akira Arai2Gang Zhu3Koichi Wakabayashi4Motohiro Okada5Shinya Ueno6Noritaka Ichinohe7Chieko Suzuki8Tomoya Kon9Masahiko Tomiyama10Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, Japan; Corresponding author at: Department of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, Japan.Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, JapanDepartment of Neurology, Aomori Prefectural Central Hospital, 2-1-1 Higashi-Tsukurimichi, Aomori 030-8551, JapanDepartment of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang 110001, ChinaDepartment of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, JapanDepartment of Neuropsychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, JapanDepartment of Neurophysiology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, JapanDepartment of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan; Ichinohe Neural System Group, Laboratory for Molecular Analysis of Higher Brain Functions, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, JapanDepartment of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, JapanDepartment of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, JapanDepartment of Neurology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zifu-cho, Hirosaki 036-8562, JapanLevo-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease; however, most patients develop uncontrollable abnormal involuntary movements known as L-DOPA-induced dyskinesia. L-DOPA-induced dyskinesia can be reduced by pallidotomy of the medial globus pallidus or pallidal deep brain stimulation, suggesting that the medial globus pallidus plays a significant role in the development of L-DOPA-induced dyskinesia. In the present study, the pathological changes of the medial globus pallidus in L-DOPA-induced dyskinesia were studied in rat models of Parkinson's disease (unilateral 6-hydroxydopamine lesioning) and L-DOPA-induced dyskinesia (L-DOPA injection in Parkinson's disease-model rats twice daily for 2 weeks, confirmed by display of dyskinesia-like abnormal involuntary movements). L-DOPA-induced dyskinesia-model rats displayed medial globus pallidus hypertrophy, enlarged axon terminals surrounding the dendrites of medial globus pallidus neurons, and increased density of synaptic vesicles in enlarged axon terminals on the lesioned side. Synaptic terminal enlargement reversed after discontinuation of L-DOPA. Histological studies revealed the enlarged synaptic terminals were those of GABAergic striatal (direct pathway) neurons. A single injection of L-DOPA enhanced GABA release in the medial globus pallidus on the lesioned side in L-DOPA-induced dyskinesia-model rats compared to Parkinson's disease-model rats. In addition, microinjection of muscimol, a GABAA receptor agonist, into the medial globus pallidus on the lesioned side of Parkinson's disease-model rats induced dyskinesia-like abnormal involuntary movements. Microinjection of bicuculline, a GABAA receptor antagonist, into the medial globus pallidus on the lesioned side alleviated L-DOPA-induced dyskinesia in Parkinson's disease-model rats that had received L-DOPA prior to the microinjection. These results indicate that priming for L-DOPA-induced dyskinesia comprises excessive GABA storage in axon terminals of the direct pathway and that expression of L-DOPA-induced dyskinesia is associated with enhanced GABA release into the medial globus pallidus after L-DOPA dosing and the resultant excessive stimulation of GABAA receptors.http://www.sciencedirect.com/science/article/pii/S0969996120302540Basal gangliaDeep brain stimulationMicrodialysisParkinson's diseaseSynaptic transmission |
| spellingShingle | Haruo Nishijima Fumiaki Mori Akira Arai Gang Zhu Koichi Wakabayashi Motohiro Okada Shinya Ueno Noritaka Ichinohe Chieko Suzuki Tomoya Kon Masahiko Tomiyama GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming Neurobiology of Disease Basal ganglia Deep brain stimulation Microdialysis Parkinson's disease Synaptic transmission |
| title | GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming |
| title_full | GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming |
| title_fullStr | GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming |
| title_full_unstemmed | GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming |
| title_short | GABA storage and release in the medial globus pallidus in L-DOPA-induced dyskinesia priming |
| title_sort | gaba storage and release in the medial globus pallidus in l dopa induced dyskinesia priming |
| topic | Basal ganglia Deep brain stimulation Microdialysis Parkinson's disease Synaptic transmission |
| url | http://www.sciencedirect.com/science/article/pii/S0969996120302540 |
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