Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia
Identifieur interne : 000266 ( Istex/Curation ); précédent : 000265; suivant : 000267Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia
Auteurs : Ana Mu Oz [France] ; Qin Li [France] ; Fabrizio Gardoni [France] ; Elena Marcello [France] ; Chuan Qin [France] ; Thomas Carlsson [France] ; Deniz Kirik [France] ; Monica Di Luca [France] ; Anders Björklund [France] ; Erwan Bezard [France, Suède] ; Manolo Carta [France, Suède]Source :
- Brain [ 0006-8950 ] ; 2008-12.
Abstract
Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT1A and 5-HT1B agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT1A and 5-HT1B agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT1A and 5-HT1B agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT1 agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT1A and 5-HT1B agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.
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DOI: 10.1093/brain/awn235
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Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Carlsson, Thomas" sort="Carlsson, Thomas" 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Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Di Luca, Monica" sort="Di Luca, Monica" uniqKey="Di Luca M" first="Monica" last="Di Luca">Monica Di Luca</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Bjorklund, Anders" sort="Bjorklund, Anders" uniqKey="Bjorklund A" first="Anders" last="Björklund">Anders Björklund</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation><country wicri:rule="url">Suède</country></affiliation></author><author><name sortKey="Carta, Manolo" sort="Carta, Manolo" uniqKey="Carta M" first="Manolo" last="Carta">Manolo Carta</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation><country wicri:rule="url">Suède</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:032298C985A68DEA77E5E46A57A4F11C97194296</idno><date when="2008" year="2008">2008</date><idno type="doi">10.1093/brain/awn235</idno><idno type="url">https://api.istex.fr/document/032298C985A68DEA77E5E46A57A4F11C97194296/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000425</idno><idno type="wicri:explorRef" wicri:stream="Istex" 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Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Li, Qin" sort="Li, Qin" uniqKey="Li Q" first="Qin" last="Li">Qin Li</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Gardoni, Fabrizio" sort="Gardoni, Fabrizio" uniqKey="Gardoni F" first="Fabrizio" last="Gardoni">Fabrizio Gardoni</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Marcello, Elena" sort="Marcello, Elena" uniqKey="Marcello E" first="Elena" last="Marcello">Elena Marcello</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Qin, Chuan" sort="Qin, Chuan" uniqKey="Qin C" first="Chuan" last="Qin">Chuan Qin</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Carlsson, Thomas" sort="Carlsson, Thomas" uniqKey="Carlsson T" first="Thomas" last="Carlsson">Thomas Carlsson</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Di Luca, Monica" sort="Di Luca, Monica" uniqKey="Di Luca M" first="Monica" last="Di Luca">Monica Di Luca</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Bjorklund, Anders" sort="Bjorklund, Anders" uniqKey="Bjorklund A" first="Anders" last="Björklund">Anders Björklund</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation><country wicri:rule="url">Suède</country></affiliation></author><author><name sortKey="Carta, Manolo" sort="Carta, Manolo" uniqKey="Carta M" first="Manolo" last="Carta">Manolo Carta</name><affiliation wicri:level="1"><mods:affiliation>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</mods:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux</wicri:regionArea></affiliation><affiliation wicri:level="1"><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation><country wicri:rule="url">Suède</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2008-12">2008-12</date><biblScope unit="volume">131</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="3380">3380</biblScope><biblScope unit="page" to="3394">3394</biblScope></imprint><idno type="ISSN">0006-8950</idno></series><idno type="istex">032298C985A68DEA77E5E46A57A4F11C97194296</idno><idno type="DOI">10.1093/brain/awn235</idno><idno type="ArticleID">awn235</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Appearance of dyskinesia is a common problem of long-term l-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for l-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT1A and 5-HT1B agonists could reduce l-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT1A and 5-HT1B agonists to counteract l-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of l-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT1A and 5-HT1B agonists in their ability to dampen l-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of l-DOPA. Furthermore, chronic administration of low doses of the 5-HT1 agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with l-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT1A and 5-HT1B agonists, particularly in combination, in dyskinetic l-DOPA-treated Parkinson's disease patients.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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