Effects of oligonucleotide antisense to dopamine D1A receptor messenger RNA in a rodent model of levodopa-induced dyskinesia
Identifieur interne : 003587 ( Main/Exploration ); précédent : 003586; suivant : 003588Effects of oligonucleotide antisense to dopamine D1A receptor messenger RNA in a rodent model of levodopa-induced dyskinesia
Auteurs : J. M. Van Kampen [Canada] ; A. J. Stoessl [Canada]Source :
- Neuroscience [ 0306-4522 ] ; 2000.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with levodopa in patients with Parkinson's disease. The pathophysiology underlying these dyskinesias remains unclear, although, it has been suggested that heightened activity of dopamine D1 receptor-bearing striatonigral neurons may play a key role. Chronic pulsatile levodopa administration to hemiparkinsonian rats results in sensitization of rotational responses to apomorphine. This sensitization is thought to be analogous to levodopa-induced dyskinesias in humans. In these studies, we further clarify the role of the dopamine D1A receptor in this rodent model of levodopa-induced dyskinesias using an in vivo oligonucleotide antisense approach. Hemiparkinsonian rats received twice daily injections of levodopa for three weeks followed by intrastriatal infusion of dopamine D1A receptor antisense (7 nmol/day, three days), a scrambled missense control sequence, or saline. Those animals treated with antisense displayed significantly fewer apomorphine-induced rotations than saline- or missense-treated controls. By reducing dopamine D1A receptor expression, we were able to attenuate sensitization of the response to apomorphine resulting from chronic pulsatile levodopa treatment. Thus, the dopamine D1A receptor appears to play a significant role in levodopa-induced dyskinesias and warrants further examination. These findings may have important implications for the development of selective treatment strategies designed to alleviate parkinsonian symptoms, while minimizing motor complications.
Affiliations:
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Stoessl</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurodegenerative Disorders Centre, Faculty of Medicine, University of British Columbia, 2221 Wesbrook Mall</s1><s2>Vancouver, B.C., V6T 2B5</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver, B.C., V6T 2B5</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">00-0396300</idno><date when="2000">2000</date><idno type="stanalyst">PASCAL 00-0396300 INIST</idno><idno type="RBID">Pascal:00-0396300</idno><idno type="wicri:Area/PascalFrancis/Corpus">000C77</idno><idno type="wicri:Area/PascalFrancis/Curation">000047</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000B95</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000B95</idno><idno type="wicri:doubleKey">0306-4522:2000:Van Kampen J:effects:of:oligonucleotide</idno><idno type="wicri:Area/Main/Merge">003B29</idno><idno type="wicri:Area/Main/Curation">003587</idno><idno type="wicri:Area/Main/Exploration">003587</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Effects of oligonucleotide antisense to dopamine D<sub>1A</sub> receptor messenger RNA in a rodent model of levodopa-induced dyskinesia</title><author><name sortKey="Van Kampen, J M" sort="Van Kampen, J M" uniqKey="Van Kampen J" first="J. M." last="Van Kampen">J. M. Van Kampen</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurodegenerative Disorders Centre, Faculty of Medicine, University of British Columbia, 2221 Wesbrook Mall</s1><s2>Vancouver, B.C., V6T 2B5</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver, B.C., V6T 2B5</wicri:noRegion></affiliation></author><author><name sortKey="Stoessl, A J" sort="Stoessl, A J" uniqKey="Stoessl A" first="A. J." last="Stoessl">A. J. Stoessl</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neurodegenerative Disorders Centre, Faculty of Medicine, University of British Columbia, 2221 Wesbrook Mall</s1><s2>Vancouver, B.C., V6T 2B5</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Vancouver, B.C., V6T 2B5</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Neuroscience</title><title level="j" type="abbreviated">Neuroscience</title><idno type="ISSN">0306-4522</idno><imprint><date when="2000">2000</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Neuroscience</title><title level="j" type="abbreviated">Neuroscience</title><idno type="ISSN">0306-4522</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal model</term><term>Antiparkinson agent</term><term>Antisense DNA</term><term>Dopamine receptor</term><term>Dyskinesia</term><term>Levodopa</term><term>Messenger RNA</term><term>Rat</term><term>Toxicity</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>DNA antisens</term><term>RNA messager</term><term>Récepteur dopaminergique</term><term>Modèle animal</term><term>Dyskinésie</term><term>Lévodopa</term><term>Toxicité</term><term>Antiparkinsonien</term><term>Rat</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with levodopa in patients with Parkinson's disease. The pathophysiology underlying these dyskinesias remains unclear, although, it has been suggested that heightened activity of dopamine D<sub>1</sub> receptor-bearing striatonigral neurons may play a key role. Chronic pulsatile levodopa administration to hemiparkinsonian rats results in sensitization of rotational responses to apomorphine. This sensitization is thought to be analogous to levodopa-induced dyskinesias in humans. In these studies, we further clarify the role of the dopamine D<sub>1A</sub> receptor in this rodent model of levodopa-induced dyskinesias using an in vivo oligonucleotide antisense approach. Hemiparkinsonian rats received twice daily injections of levodopa for three weeks followed by intrastriatal infusion of dopamine D<sub>1A</sub> receptor antisense (7 nmol/day, three days), a scrambled missense control sequence, or saline. Those animals treated with antisense displayed significantly fewer apomorphine-induced rotations than saline- or missense-treated controls. By reducing dopamine D<sub>1A</sub> receptor expression, we were able to attenuate sensitization of the response to apomorphine resulting from chronic pulsatile levodopa treatment. Thus, the dopamine D<sub>1A</sub> receptor appears to play a significant role in levodopa-induced dyskinesias and warrants further examination. These findings may have important implications for the development of selective treatment strategies designed to alleviate parkinsonian symptoms, while minimizing motor complications.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Van Kampen, J M" sort="Van Kampen, J M" uniqKey="Van Kampen J" first="J. M." last="Van Kampen">J. M. Van Kampen</name></noRegion><name sortKey="Stoessl, A J" sort="Stoessl, A J" uniqKey="Stoessl A" first="A. J." last="Stoessl">A. J. Stoessl</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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