Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease
Identifieur interne : 003A30 ( Main/Exploration ); précédent : 003A29; suivant : 003A31Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease
Auteurs : Gurdal Sahin [Suède] ; Lachlan H. Thompson [Suède, Australie] ; Sonia Lavisse ; Merve Ozgur [Suède] ; Latifa Rbah-Vidal ; Frédéric Dollé ; Philippe Hantraye ; Deniz Kirik [Suède]Source :
- PLoS ONE [ 1932-6203 ] ; 2014.
Descripteurs français
- KwdFr :
- Animaux, Benzamides, Dopamine (métabolisme), Dyskinésie due aux médicaments (anatomopathologie), Dyskinésie due aux médicaments (métabolisme), Espace extracellulaire (métabolisme), Femelle, Lévodopa (administration et posologie), Lévodopa (effets indésirables), Lévodopa (pharmacologie), Lévodopa (usage thérapeutique), Maladie de Parkinson (imagerie diagnostique), Maladie de Parkinson (métabolisme), Maladie de Parkinson (traitement médicamenteux), Microdialyse, Modèles animaux de maladie humaine, Nomifensine (usage thérapeutique), Néostriatum (), Néostriatum (métabolisme), Protéines proto-oncogènes c-fos (métabolisme), Pyrrolidines, Rat Sprague-Dawley, Récepteurs dopaminergiques (métabolisme), Sérotonine (métabolisme), Tomographie par émission de positons.
- MESH :
- administration et posologie : Lévodopa.
- anatomopathologie : Dyskinésie due aux médicaments.
- effets indésirables : Lévodopa.
- imagerie diagnostique : Maladie de Parkinson.
- métabolisme : Dopamine, Dyskinésie due aux médicaments, Espace extracellulaire, Maladie de Parkinson, Néostriatum, Protéines proto-oncogènes c-fos, Récepteurs dopaminergiques, Sérotonine.
- pharmacologie : Lévodopa.
- traitement médicamenteux : Maladie de Parkinson.
- usage thérapeutique : Lévodopa, Nomifensine.
- Animaux, Benzamides, Femelle, Microdialyse, Modèles animaux de maladie humaine, Néostriatum, Pyrrolidines, Rat Sprague-Dawley, Tomographie par émission de positons.
English descriptors
- KwdEn :
- Animals, Benzamides, Disease Models, Animal, Dopamine (metabolism), Dyskinesia, Drug-Induced (metabolism), Dyskinesia, Drug-Induced (pathology), Extracellular Space (metabolism), Female, Levodopa (administration & dosage), Levodopa (adverse effects), Levodopa (pharmacology), Levodopa (therapeutic use), Microdialysis, Neostriatum (drug effects), Neostriatum (metabolism), Nomifensine (therapeutic use), Parkinson Disease (diagnostic imaging), Parkinson Disease (drug therapy), Parkinson Disease (metabolism), Positron-Emission Tomography, Proto-Oncogene Proteins c-fos (metabolism), Pyrrolidines, Rats, Sprague-Dawley, Receptors, Dopamine (metabolism), Serotonin (metabolism).
- MESH :
- chemical , administration & dosage : Levodopa.
- chemical , adverse effects : Levodopa.
- chemical , metabolism : Dopamine, Proto-Oncogene Proteins c-fos, Receptors, Dopamine, Serotonin.
- chemical , pharmacology : Levodopa.
- chemical , therapeutic use : Levodopa, Nomifensine.
- chemical : Benzamides, Pyrrolidines.
- diagnostic imaging : Parkinson Disease.
- drug effects : Neostriatum.
- drug therapy : Parkinson Disease.
- metabolism : Dyskinesia, Drug-Induced, Extracellular Space, Neostriatum, Parkinson Disease.
- pathology : Dyskinesia, Drug-Induced.
- Animals, Disease Models, Animal, Female, Microdialysis, Positron-Emission Tomography, Rats, Sprague-Dawley.
Abstract
Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease.
Url:
DOI: 10.1371/journal.pone.0090759
PubMed: 24614598
PubMed Central: 3948692
Affiliations:
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Le document en format XML
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Science, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author><author><name sortKey="Rbah Vidal, Latifa" sort="Rbah Vidal, Latifa" uniqKey="Rbah Vidal L" first="Latifa" last="Rbah-Vidal">Latifa Rbah-Vidal</name><affiliation><nlm:aff id="aff3"><addr-line>Commissariat à l'énergie atomique (CEA), Institut d'imagerie biomédicale (I<sup>2</sup>BM), Molecular Imaging Research Center (MIRCen), Fontenay aux Roses, France</addr-line></nlm:aff><wicri:noCountry code="subfield">Institut d'imagerie biomédicale (I</wicri:noCountry></affiliation></author><author><name sortKey="Dolle, Frederic" sort="Dolle, Frederic" uniqKey="Dolle F" first="Frédéric" last="Dollé">Frédéric Dollé</name><affiliation><nlm:aff id="aff4"><addr-line>Commissariat à l'énergie atomique (CEA), Institut d'imagerie biomédicale (I<sup>2</sup>BM), Service Hospitalier Frédéric Joliot, Orsay, France</addr-line></nlm:aff><wicri:noCountry code="subfield">Institut d'imagerie biomédicale (I</wicri:noCountry></affiliation></author><author><name sortKey="Hantraye, Philippe" sort="Hantraye, Philippe" uniqKey="Hantraye P" first="Philippe" last="Hantraye">Philippe Hantraye</name><affiliation><nlm:aff id="aff3"><addr-line>Commissariat à l'énergie atomique (CEA), Institut d'imagerie biomédicale (I<sup>2</sup>BM), Molecular Imaging Research Center (MIRCen), Fontenay aux Roses, France</addr-line></nlm:aff><wicri:noCountry code="subfield">Institut d'imagerie biomédicale (I</wicri:noCountry></affiliation></author><author><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Brain Repair And Imaging in Neural Systems (BRAINS) Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Brain Repair And Imaging in Neural Systems (BRAINS) Unit, Department of Experimental Medical Science, Lund University, Lund</wicri:regionArea><wicri:noRegion>Lund</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Benzamides</term><term>Disease Models, Animal</term><term>Dopamine (metabolism)</term><term>Dyskinesia, Drug-Induced (metabolism)</term><term>Dyskinesia, Drug-Induced (pathology)</term><term>Extracellular Space (metabolism)</term><term>Female</term><term>Levodopa (administration & dosage)</term><term>Levodopa (adverse effects)</term><term>Levodopa (pharmacology)</term><term>Levodopa (therapeutic use)</term><term>Microdialysis</term><term>Neostriatum (drug effects)</term><term>Neostriatum (metabolism)</term><term>Nomifensine (therapeutic use)</term><term>Parkinson Disease (diagnostic imaging)</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (metabolism)</term><term>Positron-Emission Tomography</term><term>Proto-Oncogene Proteins c-fos (metabolism)</term><term>Pyrrolidines</term><term>Rats, Sprague-Dawley</term><term>Receptors, Dopamine (metabolism)</term><term>Serotonin (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Benzamides</term><term>Dopamine (métabolisme)</term><term>Dyskinésie due aux médicaments (anatomopathologie)</term><term>Dyskinésie due aux médicaments (métabolisme)</term><term>Espace extracellulaire (métabolisme)</term><term>Femelle</term><term>Lévodopa (administration et posologie)</term><term>Lévodopa (effets indésirables)</term><term>Lévodopa (pharmacologie)</term><term>Lévodopa (usage thérapeutique)</term><term>Maladie de Parkinson (imagerie diagnostique)</term><term>Maladie de Parkinson (métabolisme)</term><term>Maladie de Parkinson (traitement médicamenteux)</term><term>Microdialyse</term><term>Modèles animaux de maladie humaine</term><term>Nomifensine (usage thérapeutique)</term><term>Néostriatum ()</term><term>Néostriatum (métabolisme)</term><term>Protéines proto-oncogènes c-fos (métabolisme)</term><term>Pyrrolidines</term><term>Rat Sprague-Dawley</term><term>Récepteurs dopaminergiques (métabolisme)</term><term>Sérotonine (métabolisme)</term><term>Tomographie par émission de positons</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Levodopa</term></keywords><keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en"><term>Levodopa</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Dopamine</term><term>Proto-Oncogene Proteins c-fos</term><term>Receptors, Dopamine</term><term>Serotonin</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Levodopa</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Levodopa</term><term>Nomifensine</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Benzamides</term><term>Pyrrolidines</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Lévodopa</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Dyskinésie due aux médicaments</term></keywords><keywords scheme="MESH" qualifier="diagnostic imaging" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Neostriatum</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="effets indésirables" xml:lang="fr"><term>Lévodopa</term></keywords><keywords scheme="MESH" qualifier="imagerie diagnostique" xml:lang="fr"><term>Maladie de Parkinson</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>Extracellular Space</term><term>Neostriatum</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Dopamine</term><term>Dyskinésie due aux médicaments</term><term>Espace extracellulaire</term><term>Maladie de Parkinson</term><term>Néostriatum</term><term>Protéines proto-oncogènes c-fos</term><term>Récepteurs dopaminergiques</term><term>Sérotonine</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Lévodopa</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Maladie de Parkinson</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Lévodopa</term><term>Nomifensine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Female</term><term>Microdialysis</term><term>Positron-Emission Tomography</term><term>Rats, Sprague-Dawley</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Benzamides</term><term>Femelle</term><term>Microdialyse</term><term>Modèles animaux de maladie humaine</term><term>Néostriatum</term><term>Pyrrolidines</term><term>Rat Sprague-Dawley</term><term>Tomographie par émission de positons</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Fahn, S" uniqKey="Fahn S">S Fahn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Ds" uniqKey="Kim D">DS Kim</name></author><author><name sortKey="Palmiter, Rd" uniqKey="Palmiter R">RD Palmiter</name></author><author><name sortKey="Cummins, A" uniqKey="Cummins A">A Cummins</name></author><author><name sortKey="Gerfen, Cr" uniqKey="Gerfen C">CR Gerfen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Winkler, C" uniqKey="Winkler C">C Winkler</name></author><author><name sortKey="Kirik, D" uniqKey="Kirik D">D Kirik</name></author><author><name sortKey="Bjorklund, A" uniqKey="Bjorklund A">A Bjorklund</name></author><author><name 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C">C Winkler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Andersson, M" uniqKey="Andersson M">M Andersson</name></author><author><name sortKey="Hilbertson, A" uniqKey="Hilbertson A">A Hilbertson</name></author><author><name sortKey="Cenci, Ma" uniqKey="Cenci M">MA Cenci</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pavon, N" uniqKey="Pavon N">N Pavon</name></author><author><name sortKey="Martin, Ab" uniqKey="Martin A">AB Martin</name></author><author><name sortKey="Mendialdua, A" uniqKey="Mendialdua A">A Mendialdua</name></author><author><name sortKey="Moratalla, R" uniqKey="Moratalla R">R Moratalla</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cao, X" uniqKey="Cao X">X Cao</name></author><author><name sortKey="Yasuda, T" uniqKey="Yasuda T">T Yasuda</name></author><author><name sortKey="Uthayathas, S" uniqKey="Uthayathas S">S Uthayathas</name></author><author><name sortKey="Watts, Rl" uniqKey="Watts R">RL Watts</name></author><author><name sortKey="Mouradian, Mm" uniqKey="Mouradian M">MM Mouradian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moratalla, R" uniqKey="Moratalla R">R Moratalla</name></author><author><name sortKey="Elibol, B" uniqKey="Elibol B">B Elibol</name></author><author><name sortKey="Vallejo, M" uniqKey="Vallejo M">M Vallejo</name></author><author><name sortKey="Graybiel, Am" uniqKey="Graybiel A">AM Graybiel</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Australie</li><li>Suède</li></country><region><li>Victoria (État)</li></region><settlement><li>Melbourne</li></settlement><orgName><li>Université de Melbourne</li></orgName></list><tree><noCountry><name sortKey="Dolle, Frederic" sort="Dolle, Frederic" uniqKey="Dolle F" first="Frédéric" last="Dollé">Frédéric Dollé</name><name sortKey="Hantraye, Philippe" sort="Hantraye, Philippe" uniqKey="Hantraye P" first="Philippe" last="Hantraye">Philippe Hantraye</name><name sortKey="Lavisse, Sonia" sort="Lavisse, Sonia" uniqKey="Lavisse S" first="Sonia" last="Lavisse">Sonia Lavisse</name><name sortKey="Rbah Vidal, Latifa" sort="Rbah Vidal, Latifa" uniqKey="Rbah Vidal L" first="Latifa" last="Rbah-Vidal">Latifa Rbah-Vidal</name></noCountry><country name="Suède"><noRegion><name sortKey="Sahin, Gurdal" sort="Sahin, Gurdal" uniqKey="Sahin G" first="Gurdal" last="Sahin">Gurdal Sahin</name></noRegion><name sortKey="Kirik, Deniz" sort="Kirik, Deniz" uniqKey="Kirik D" first="Deniz" last="Kirik">Deniz Kirik</name><name sortKey="Ozgur, Merve" sort="Ozgur, Merve" uniqKey="Ozgur M" first="Merve" last="Ozgur">Merve Ozgur</name><name sortKey="Thompson, Lachlan H" sort="Thompson, Lachlan H" uniqKey="Thompson L" first="Lachlan H." last="Thompson">Lachlan H. Thompson</name></country><country name="Australie"><region name="Victoria (État)"><name sortKey="Thompson, Lachlan H" sort="Thompson, Lachlan H" uniqKey="Thompson L" first="Lachlan H." last="Thompson">Lachlan H. Thompson</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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