Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats
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Abstract
BACKGROUND: The gold standard for symptomatic relief of Parkinson's disease (PD) is L-DOPA. However, long-term treatment often leads to motor complications such as L-DOPA-induced dyskinesia (LID). While amantadine (Gocovri™) is the only approved therapy for dyskinesia in PD patients on the American market, it is associated with neurological side effects and limited efficacy. Thus, there remains a high unmet need for addressing LID in PD patients worldwide. OBJECTIVE: The objective of this study was to evaluate the efficacy, safety and performance compared to approved treatments of the serotonin receptor 1A (5-HT1A) and 5-HT1B/D agonists buspirone and zolmitriptan in the 6-hydroxydopamine unilaterally lesioned rat model for PD. METHODS: The hemiparkinsonian 6-OHDA-lesioned rats underwent chronic treatment with L-DOPA to induce dyskinesia and were subsequently used for efficacy testing of buspirone, zolmitriptan and comparison with amantadine, measured as abnormal involuntary movement (AIM) scores after L-DOPA challenge. Safety testing was performed in model and naïve animals using forelimb adjusting, rotarod and open field tests. RESULTS: 5-HT1A and 5-HT1B/D agonism effectively reduced AIM scores in a synergistic manner. The drug combination of buspirone and zolmitriptan was safe and did not lead to tolerance development following sub-chronic administration. Head-to-head comparison with amantadine showed superior performance of buspirone and zolmitriptan in the model. CONCLUSIONS: The strong anti-dyskinetic effect found with combined 5-HT1A and 5-HT1B/D agonism renders buspirone and zolmitriptan together a meaningful treatment for LID in PD.
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6-OHDA is commonly administered to the striatum via stereotaxic injection due to the blood-brain barrier's impermeability to the compound.
“6-OHDA is commonly administered to the striatum via stereotaxic injection due to BBB's impermeability to the compound [75]”
From Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity <i>via</i> AMPK/SOD2 Pathway (2023) · cites this paper as [75]
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Pros and cons of narrow- versus wide-compartment rotarod apparatus: An experimental study in mice
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Buspirone and Zolmitriptan Combination for Dyskinesia: A Randomized, Controlled, Crossover Study
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Role of P11 through serotonergic and glutamatergic pathways in LID
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Aberrant Gamma Oscillations in Parkinson’s Disease
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- Authors
- Thomsen, M., Stoica, A., Christensen, K. V., Fryland, T., Mikkelsen, J. D., & Hansen, J. B.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Christensen, Kenneth Vielsted
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 358
- Pages
- 114209
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W4292241575
- Cited by
- 8
- References
- 127
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 2
- FWCI
- 0.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Experimental Neurology (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- levodopa-induced dyskinesia, Parkinson's disease, buspirone, zolmitriptan, amantadine, 6-hydroxydopamine lesion, hemiparkinsonian rat model, abnormal involuntary movements, drug synergy, drug safety
- MeSH terms
- Amantadine, Animals, Antiparkinson Agents, Buspirone, Dyskinesia, Drug-Induced, Levodopa, Parkinson Disease, Receptors, Serotonin, Serotonin, Tryptamines, Oxidopamine, Rats, Sprague-Dawley, Oxazolidinones, Rats, Serotonin 5-HT1 Receptor Agonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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