The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease
Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modula...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-10-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/9/10/2265 |
| _version_ | 1797551457009926144 |
|---|---|
| author | Feras Altwal Connor Moon Anthony R. West Heinz Steiner |
| author_facet | Feras Altwal Connor Moon Anthony R. West Heinz Steiner |
| author_sort | Feras Altwal |
| collection | DOAJ |
| description | Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects. |
| first_indexed | 2024-03-10T15:45:22Z |
| format | Article |
| id | doaj.art-001d813913a943428ef1453501053d45 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T15:45:22Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-001d813913a943428ef1453501053d452023-11-20T16:29:11ZengMDPI AGCells2073-44092020-10-01910226510.3390/cells9102265The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s DiseaseFeras Altwal0Connor Moon1Anthony R. West2Heinz Steiner3Center for Neurodegenerative Disease & Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USAStanson Toshok Center for Brain Function and Repair, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USACenter for Neurodegenerative Disease & Therapeutics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USAStanson Toshok Center for Brain Function and Repair, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USALevodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.https://www.mdpi.com/2073-4409/9/10/2265dopamineserotoningene expressionL-DOPAantidepressantstriatum |
| spellingShingle | Feras Altwal Connor Moon Anthony R. West Heinz Steiner The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease Cells dopamine serotonin gene expression L-DOPA antidepressant striatum |
| title | The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease |
| title_full | The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease |
| title_fullStr | The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease |
| title_full_unstemmed | The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease |
| title_short | The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease |
| title_sort | multimodal serotonergic agent vilazodone inhibits l dopa induced gene regulation in striatal projection neurons and associated dyskinesia in an animal model of parkinson s disease |
| topic | dopamine serotonin gene expression L-DOPA antidepressant striatum |
| url | https://www.mdpi.com/2073-4409/9/10/2265 |
| work_keys_str_mv | AT ferasaltwal themultimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease AT connormoon themultimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease AT anthonyrwest themultimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease AT heinzsteiner themultimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease AT ferasaltwal multimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease AT connormoon multimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease AT anthonyrwest multimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease AT heinzsteiner multimodalserotonergicagentvilazodoneinhibitsldopainducedgeneregulationinstriatalprojectionneuronsandassociateddyskinesiainananimalmodelofparkinsonsdisease |