Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia
Identifieur interne : 000425 ( Istex/Corpus ); précédent : 000424; suivant : 000426Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia
Auteurs : Ana Mu Oz ; Qin Li ; Fabrizio Gardoni ; Elena Marcello ; Chuan Qin ; Thomas Carlsson ; Deniz Kirik ; Monica Di Luca ; Anders Björklund ; Erwan Bezard ; Manolo CartaSource :
- 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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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></affiliation></author><author><name sortKey="Carlsson, Thomas" sort="Carlsson, Thomas" uniqKey="Carlsson T" first="Thomas" last="Carlsson">Thomas Carlsson</name><affiliation><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></affiliation></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Bjorklund, Anders" sort="Bjorklund, Anders" uniqKey="Bjorklund A" first="Anders" last="Björklund">Anders Björklund</name><affiliation><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></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation><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></affiliation><affiliation><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation></affiliation></author><author><name sortKey="Carta, Manolo" sort="Carta, Manolo" uniqKey="Carta M" first="Manolo" last="Carta">Manolo Carta</name><affiliation><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></affiliation><affiliation><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation></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" wicri:step="Corpus" wicri:corpus="ISTEX">000425</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia</title><author><name sortKey="Mu Oz, Ana" sort="Mu Oz, Ana" uniqKey="Mu Oz A" first="Ana" last="Mu Oz">Ana Mu Oz</name><affiliation><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></affiliation></author><author><name sortKey="Li, Qin" sort="Li, Qin" uniqKey="Li Q" first="Qin" last="Li">Qin Li</name><affiliation><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></affiliation></author><author><name sortKey="Gardoni, Fabrizio" sort="Gardoni, Fabrizio" uniqKey="Gardoni F" first="Fabrizio" last="Gardoni">Fabrizio Gardoni</name><affiliation><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></affiliation></author><author><name sortKey="Marcello, Elena" sort="Marcello, Elena" uniqKey="Marcello E" first="Elena" last="Marcello">Elena Marcello</name><affiliation><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></affiliation></author><author><name sortKey="Qin, Chuan" sort="Qin, Chuan" uniqKey="Qin C" first="Chuan" last="Qin">Chuan Qin</name><affiliation><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></affiliation></author><author><name sortKey="Carlsson, Thomas" sort="Carlsson, Thomas" uniqKey="Carlsson T" first="Thomas" last="Carlsson">Thomas Carlsson</name><affiliation><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></affiliation></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><affiliation><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></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><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></affiliation></author><author><name sortKey="Bjorklund, Anders" sort="Bjorklund, Anders" uniqKey="Bjorklund A" first="Anders" last="Björklund">Anders Björklund</name><affiliation><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></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation><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></affiliation><affiliation><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation></affiliation></author><author><name sortKey="Carta, Manolo" sort="Carta, Manolo" uniqKey="Carta M" first="Manolo" last="Carta">Manolo Carta</name><affiliation><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></affiliation><affiliation><mods:affiliation>E-mail: Manolo.Carta@med.lu.se</mods:affiliation></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><istex><corpusName>oup</corpusName><author><json:item><name>Ana Muñoz</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Qin Li</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Fabrizio Gardoni</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Elena Marcello</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Chuan Qin</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Thomas Carlsson</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Deniz Kirik</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Monica Di Luca</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Anders Björklund</name><affiliations><json:string>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</json:string></affiliations></json:item><json:item><name>Erwan Bezard</name><affiliations><json:string>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</json:string><json:string>E-mail: Manolo.Carta@med.lu.se</json:string></affiliations></json:item><json:item><name>Manolo Carta</name><affiliations><json:string>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</json:string><json:string>E-mail: Manolo.Carta@med.lu.se</json:string></affiliations></json:item></author><subject><json:item><value>Original Articles</value></json:item><json:item><value>L-DOPA</value></json:item><json:item><value>Dyskinesia</value></json:item><json:item><value>Parkinson's disease</value></json:item><json:item><value>Serotonin agonists</value></json:item><json:item><value>MPTP monkeys</value></json:item></subject><articleId><json:string>awn235</json:string></articleId><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><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.</abstract><qualityIndicators><score>9.88</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612.68 x 790.866 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>1775</abstractCharCount><pdfWordCount>10859</pdfWordCount><pdfCharCount>67213</pdfCharCount><pdfPageCount>15</pdfPageCount><abstractWordCount>240</abstractWordCount></qualityIndicators><title>Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia</title><genre><json:string>research-article</json:string></genre><host><volume>131</volume><publisherId><json:string>brainj</json:string></publisherId><pages><last>3394</last><first>3380</first></pages><issn><json:string>0006-8950</json:string></issn><issue>12</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2156</json:string></eissn><title>Brain</title></host><publicationDate>2008</publicationDate><copyrightDate>2008</copyrightDate><doi><json:string>10.1093/brain/awn235</json:string></doi><id>032298C985A68DEA77E5E46A57A4F11C97194296</id><score>0.10900164</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/032298C985A68DEA77E5E46A57A4F11C97194296/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/032298C985A68DEA77E5E46A57A4F11C97194296/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/032298C985A68DEA77E5E46A57A4F11C97194296/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</p></availability><date>2008-10-24</date></publicationStmt><notesStmt><note>*These authors contributed equally to this work.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia</title><author xml:id="author-1"><persName><forename type="first">Ana</forename><surname>Muñoz</surname></persName><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</affiliation></author><author xml:id="author-2"><persName><forename type="first">Qin</forename><surname>Li</surname></persName><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</affiliation></author><author xml:id="author-3"><persName><forename type="first">Fabrizio</forename><surname>Gardoni</surname></persName><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</affiliation></author><author xml:id="author-4"><persName><forename type="first">Elena</forename><surname>Marcello</surname></persName><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</affiliation></author><author xml:id="author-5"><persName><forename type="first">Chuan</forename><surname>Qin</surname></persName><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</affiliation></author><author xml:id="author-6"><persName><forename type="first">Thomas</forename><surname>Carlsson</surname></persName><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</affiliation></author><author xml:id="author-7"><persName><forename type="first">Deniz</forename><surname>Kirik</surname></persName><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</affiliation></author><author xml:id="author-8"><persName><forename type="first">Monica</forename><surname>Di Luca</surname></persName><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</affiliation></author><author xml:id="author-9"><persName><forename type="first">Anders</forename><surname>Björklund</surname></persName><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</affiliation></author><author xml:id="author-10" corresp="yes"><persName><forename type="first">Erwan</forename><surname>Bezard</surname></persName><email>Manolo.Carta@med.lu.se</email><note type="biography">*These authors contributed equally to this work.</note><affiliation>*These authors contributed equally to this work.</affiliation><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</affiliation></author><author xml:id="author-11" corresp="yes"><persName><forename type="first">Manolo</forename><surname>Carta</surname></persName><email>Manolo.Carta@med.lu.se</email><note type="biography">*These authors contributed equally to this work.</note><affiliation>*These authors contributed equally to this work.</affiliation><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</affiliation></author></analytic><monogr><title level="j">Brain</title><idno type="pISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="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></monogr><idno type="istex">032298C985A68DEA77E5E46A57A4F11C97194296</idno><idno type="DOI">10.1093/brain/awn235</idno><idno type="ArticleID">awn235</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008-10-24</date></creation><abstract><p>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.</p></abstract><textClass><keywords scheme="keyword"><list><item><term>Original Articles</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>L-DOPA</term></item><item><term>Dyskinesia</term></item><item><term>Parkinson's disease</term></item><item><term>Serotonin agonists</term></item><item><term>MPTP monkeys</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2008-10-24">Created</change><change when="2008-12">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/032298C985A68DEA77E5E46A57A4F11C97194296/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">brain</journal-id><journal-id journal-id-type="publisher-id">brainj</journal-id><journal-title>Brain</journal-title><issn pub-type="ppub">0006-8950</issn><issn pub-type="epub">1460-2156</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/brain/awn235</article-id><article-id pub-id-type="publisher-id">awn235</article-id><article-categories><subj-group><subject>Original Articles</subject></subj-group></article-categories><title-group><article-title>Combined 5-HT<sub>1A</sub> and 5-HT<sub>1B</sub> receptor agonists for the treatment of <sc>l</sc>-DOPA-induced dyskinesia</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Muñoz</surname><given-names>Ana</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Qin</given-names></name><xref ref-type="aff" rid="AFF1"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gardoni</surname><given-names>Fabrizio</given-names></name><xref ref-type="aff" rid="AFF1"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Marcello</surname><given-names>Elena</given-names></name><xref ref-type="aff" rid="AFF1"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Qin</surname><given-names>Chuan</given-names></name><xref ref-type="aff" rid="AFF1"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Carlsson</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref ref-type="aff" rid="AFF1"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kirik</surname><given-names>Deniz</given-names></name><xref ref-type="aff" rid="AFF1"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Di Luca</surname><given-names>Monica</given-names></name><xref ref-type="aff" rid="AFF1"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Björklund</surname><given-names>Anders</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Bezard</surname><given-names>Erwan</given-names></name><xref ref-type="aff" rid="AFF1"><sup>5</sup></xref><xref ref-type="fn" rid="FN1">*</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Carta</surname><given-names>Manolo</given-names></name><xref ref-type="aff" rid="AFF1"><sup>1</sup></xref><xref ref-type="aff" rid="AFF1"><sup>4</sup></xref><xref ref-type="fn" rid="FN1">*</xref></contrib></contrib-group><aff id="AFF1"><sup>1</sup>Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, Sweden, <sup>2</sup>Institute of Lab Animal Sciences, China Academy of Medical Sciences, Beijing, China, <sup>3</sup>Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milano, Italy, <sup>4</sup>Brain Repair and Imaging in Neural Systems Unit, Section for Neuroscience, Department of Experimental Medical Science, University of Lund, Sweden and <sup>5</sup>University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France</aff><author-notes><fn id="FN1"><p>*These authors contributed equally to this work.</p></fn><corresp>Correspondence to: Manolo Carta, Neurobiology Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, University of Lund, 22184 Lund, Sweden and Erwan Bezard, University Victor Segalen Bordeaux 2, Centre National de la Recherche Scientifique, Bordeaux Institute of Neuroscience, UMR 5227, Bordeaux, France E-mail: <email>Manolo.Carta@med.lu.se</email> and <email>erwan.bezard@u-bordeaux2.fr</email></corresp></author-notes><pub-date pub-type="ppub"><month>12</month><year>2008</year></pub-date><pub-date pub-type="epub"><day>24</day><month>10</month><year>2008</year></pub-date><volume>131</volume><issue>12</issue><fpage>3380</fpage><lpage>3394</lpage><history><date date-type="received"><day>16</day><month>5</month><year>2008</year></date><date date-type="rev-recd"><day>22</day><month>8</month><year>2008</year></date><date date-type="accepted"><day>29</day><month>8</month><year>2008</year></date></history><permissions><copyright-statement>© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2008</copyright-year></permissions><abstract><p>Appearance of dyskinesia is a common problem of long-term <sc>l</sc>-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 <sc>l</sc>-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HT<sub>1A</sub> and 5-HT<sub>1B</sub> agonists could reduce <sc>l</sc>-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HT<sub>1A</sub> and 5-HT<sub>1B</sub> agonists to counteract <sc>l</sc>-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 <sc>l</sc>-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HT<sub>1A</sub> and 5-HT<sub>1B</sub> agonists in their ability to dampen <sc>l</sc>-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 <sc>l</sc>-DOPA. Furthermore, chronic administration of low doses of the 5-HT<sub>1</sub> agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with <sc>l</sc>-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HT<sub>1A</sub> and 5-HT<sub>1B</sub> agonists, particularly in combination, in dyskinetic <sc>l</sc>-DOPA-treated Parkinson's disease patients.</p></abstract><kwd-group><kwd><sc>L</sc>-DOPA</kwd><kwd>Dyskinesia</kwd><kwd>Parkinson's disease</kwd><kwd>Serotonin agonists</kwd><kwd>MPTP monkeys</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Combined 5-HT1A and 5-HT1B receptor agonists for the treatment of l-DOPA-induced dyskinesia</title></titleInfo><name type="personal"><namePart type="given">Ana</namePart><namePart type="family">Muñoz</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Qin</namePart><namePart type="family">Li</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fabrizio</namePart><namePart type="family">Gardoni</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Elena</namePart><namePart type="family">Marcello</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chuan</namePart><namePart type="family">Qin</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Carlsson</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Deniz</namePart><namePart type="family">Kirik</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Monica</namePart><namePart type="family">Di Luca</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anders</namePart><namePart type="family">Björklund</namePart><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</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Erwan</namePart><namePart type="family">Bezard</namePart><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</affiliation><affiliation>E-mail: Manolo.Carta@med.lu.se</affiliation><description>*These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Manolo</namePart><namePart type="family">Carta</namePart><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</affiliation><affiliation>E-mail: Manolo.Carta@med.lu.se</affiliation><description>*These authors contributed equally to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><subject><topic>Original Articles</topic></subject><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2008-12</dateIssued><dateCreated encoding="w3cdtf">2008-10-24</dateCreated><copyrightDate encoding="w3cdtf">2008</copyrightDate></originInfo><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><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.</abstract><note type="footnotes">*These authors contributed equally to this work.</note><subject><genre>keywords</genre><topic>L-DOPA</topic><topic>Dyskinesia</topic><topic>Parkinson's disease</topic><topic>Serotonin agonists</topic><topic>MPTP monkeys</topic></subject><relatedItem type="host"><titleInfo><title>Brain</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0006-8950</identifier><identifier type="eISSN">1460-2156</identifier><identifier type="PublisherID">brainj</identifier><identifier type="PublisherID-hwp">brain</identifier><part><date>2008</date><detail type="volume"><caption>vol.</caption><number>131</number></detail><detail type="issue"><caption>no.</caption><number>12</number></detail><extent unit="pages"><start>3380</start><end>3394</end></extent></part></relatedItem><identifier type="istex">032298C985A68DEA77E5E46A57A4F11C97194296</identifier><identifier type="DOI">10.1093/brain/awn235</identifier><identifier type="ArticleID">awn235</identifier><accessCondition type="use and reproduction" contentType="copyright">© The Author (2008). 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