Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia
Introduction: The leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT1A biased agonist, h...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | NeuroImage: Clinical |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213158223001882 |
| _version_ | 1797736880943398912 |
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| author | Sarah Chaib Benjamin Vidal Caroline Bouillot Ronan Depoortere Adrian Newman-Tancredi Luc Zimmer Elise Levigoureux |
| author_facet | Sarah Chaib Benjamin Vidal Caroline Bouillot Ronan Depoortere Adrian Newman-Tancredi Luc Zimmer Elise Levigoureux |
| author_sort | Sarah Chaib |
| collection | DOAJ |
| description | Introduction: The leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT1A biased agonist, has robust antidyskinetic effects. Here, we investigated its effects in hemiparkinsonian (HPK) rats with a unilateral nigrostriatal 6-OHDA lesion. Methods: We compared HPK rats with LID (i.e., sensitized to the dyskinetic effects of chronic L-DOPA) and without LID (HPK-non-LID), using [18F]FDG PET imaging and fMRI functional connectivity following systemic treatment with saline, L-DOPA, NLX-112 or L-DOPA + NLX-112. Results: In HPK-non-LID rats, [18F]FDG PET experiments showed that L-DOPA led to hypermetabolism in motor areas (cerebellum, brainstem, and mesencephalic locomotor region) and to hypometabolism in cortical regions. L-DOPA effects were also observed in HPK-LID rats, with the additional emergence of hypermetabolism in raphe nuclei and hypometabolism in hippocampus and striatum. NLX-112 attenuated L-DOPA-induced raphe hypermetabolism and cingulate cortex hypometabolism in HPK-LID rats. Moreover, in fMRI experiments NLX-112 partially corrected the altered neural circuit connectivity profile in HPK-LID rats, through activity in regions rich in 5-HT1A receptors. Conclusion: This neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT1A receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson’s disease. |
| first_indexed | 2024-03-12T13:19:34Z |
| format | Article |
| id | doaj.art-96c2dadb0cb244a6b8ae37d32e96c777 |
| institution | Directory Open Access Journal |
| issn | 2213-1582 |
| language | English |
| last_indexed | 2024-03-12T13:19:34Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | NeuroImage: Clinical |
| spelling | doaj.art-96c2dadb0cb244a6b8ae37d32e96c7772023-08-26T04:43:18ZengElsevierNeuroImage: Clinical2213-15822023-01-0139103497Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesiaSarah Chaib0Benjamin Vidal1Caroline Bouillot2Ronan Depoortere3Adrian Newman-Tancredi4Luc Zimmer5Elise Levigoureux6Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Lyon, FranceUniversité Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, FranceCERMEP-Imaging Platform, Bron, FranceNeurolixis, Castres, FranceNeurolixis, Castres, FranceUniversité Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Lyon, France; CERMEP-Imaging Platform, Bron, France; Corresponding author at: Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France.Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Lyon, FranceIntroduction: The leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT1A biased agonist, has robust antidyskinetic effects. Here, we investigated its effects in hemiparkinsonian (HPK) rats with a unilateral nigrostriatal 6-OHDA lesion. Methods: We compared HPK rats with LID (i.e., sensitized to the dyskinetic effects of chronic L-DOPA) and without LID (HPK-non-LID), using [18F]FDG PET imaging and fMRI functional connectivity following systemic treatment with saline, L-DOPA, NLX-112 or L-DOPA + NLX-112. Results: In HPK-non-LID rats, [18F]FDG PET experiments showed that L-DOPA led to hypermetabolism in motor areas (cerebellum, brainstem, and mesencephalic locomotor region) and to hypometabolism in cortical regions. L-DOPA effects were also observed in HPK-LID rats, with the additional emergence of hypermetabolism in raphe nuclei and hypometabolism in hippocampus and striatum. NLX-112 attenuated L-DOPA-induced raphe hypermetabolism and cingulate cortex hypometabolism in HPK-LID rats. Moreover, in fMRI experiments NLX-112 partially corrected the altered neural circuit connectivity profile in HPK-LID rats, through activity in regions rich in 5-HT1A receptors. Conclusion: This neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT1A receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson’s disease.http://www.sciencedirect.com/science/article/pii/S2213158223001882FDGfMRISerotoninLevodopa-induced dyskinesiaBiased agonist |
| spellingShingle | Sarah Chaib Benjamin Vidal Caroline Bouillot Ronan Depoortere Adrian Newman-Tancredi Luc Zimmer Elise Levigoureux Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia NeuroImage: Clinical FDG fMRI Serotonin Levodopa-induced dyskinesia Biased agonist |
| title | Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia |
| title_full | Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia |
| title_fullStr | Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia |
| title_full_unstemmed | Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia |
| title_short | Multimodal imaging study of the 5-HT1A receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia |
| title_sort | multimodal imaging study of the 5 ht1a receptor biased agonist nlx 112 in a model of l dopa induced dyskinesia |
| topic | FDG fMRI Serotonin Levodopa-induced dyskinesia Biased agonist |
| url | http://www.sciencedirect.com/science/article/pii/S2213158223001882 |
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