Selective blockade of D3 dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate
Identifieur interne : 000268 ( France/Analysis ); précédent : 000267; suivant : 000269Selective blockade of D3 dopamine receptors enhances the anti-parkinsonian properties of ropinirole and levodopa in the MPTP-lesioned primate
Auteurs : M. A. Silverdale [Royaume-Uni] ; S. L. Nicholson [Royaume-Uni] ; P. Ravenscroft [Royaume-Uni] ; A. R. Crossman [Royaume-Uni] ; M. J. Millan [France] ; J. M. Brotchie [Canada]Source :
- Experimental neurology : (Print) [ 0014-4886 ] ; 2004.
Descripteurs français
- Pascal (Inist)
- Parkinson maladie, Récepteur dopaminergique D3, Ropinirole, Dyskinésie, Lévodopa, Primates, Antagoniste dopamine, Traitement, Sélectivité, Etude comparative, Récepteur dopaminergique D2, Dose faible, Récepteur dopaminergique, Stimulant dopaminergique, Conduite à tenir, Homme, Dopamine, Noyau gris central, Contrôle moteur.
- Wicri :
- topic : Homme.
English descriptors
- KwdEn :
Abstract
To date, the lack of highly selective antagonists at the dopamine D3receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D3 versus D2 receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D3-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses. S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D3 receptor stimulation. Indeed, stimulation of D3 receptors may be detrimental to the anti-parkinsonian properties of D2/D3 agonists. Selectivity for stimulation of D2, over D3, receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia.
Affiliations:
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A." last="Silverdale">M. A. Silverdale</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Manchester Movement Disorder Laboratory, School of Biological Sciences, University of Manchester, Oxford Road</s1><s2>Manchester M13 9PT</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M13 9PT</wicri:noRegion><orgName type="university">Université de Manchester</orgName><placeName><settlement type="city">Manchester</settlement><region type="nation">Angleterre</region><region nuts="2" type="region">Grand Manchester</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neurology, Hope Hospital</s1><s2>Salford M6 8HD</s2><s3>GBR</s3><sZ>1 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Salford M6 8HD</wicri:noRegion></affiliation></author><author><name sortKey="Nicholson, S L" sort="Nicholson, S L" uniqKey="Nicholson S" first="S. L." last="Nicholson">S. L. Nicholson</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Manchester Movement Disorder Laboratory, School of Biological Sciences, University of Manchester, Oxford Road</s1><s2>Manchester M13 9PT</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M13 9PT</wicri:noRegion><orgName type="university">Université de Manchester</orgName><placeName><settlement type="city">Manchester</settlement><region type="nation">Angleterre</region><region nuts="2" type="region">Grand Manchester</region></placeName></affiliation></author><author><name sortKey="Ravenscroft, P" sort="Ravenscroft, P" uniqKey="Ravenscroft P" first="P." last="Ravenscroft">P. Ravenscroft</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Manchester Movement Disorder Laboratory, School of Biological Sciences, University of Manchester, Oxford Road</s1><s2>Manchester M13 9PT</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M13 9PT</wicri:noRegion><orgName type="university">Université de Manchester</orgName><placeName><settlement type="city">Manchester</settlement><region type="nation">Angleterre</region><region nuts="2" type="region">Grand Manchester</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Motac Neuroscience Ltd., Williams House</s1><s2>Manchester M15 6SE</s2><s3>GBR</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M15 6SE</wicri:noRegion></affiliation></author><author><name sortKey="Crossman, A R" sort="Crossman, A R" uniqKey="Crossman A" first="A. R." last="Crossman">A. R. Crossman</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Manchester Movement Disorder Laboratory, School of Biological Sciences, University of Manchester, Oxford Road</s1><s2>Manchester M13 9PT</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M13 9PT</wicri:noRegion><orgName type="university">Université de Manchester</orgName><placeName><settlement type="city">Manchester</settlement><region type="nation">Angleterre</region><region nuts="2" type="region">Grand Manchester</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Motac Neuroscience Ltd., Williams House</s1><s2>Manchester M15 6SE</s2><s3>GBR</s3><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Manchester M15 6SE</wicri:noRegion></affiliation></author><author><name sortKey="Millan, M J" sort="Millan, M J" uniqKey="Millan M" first="M. J." last="Millan">M. J. Millan</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy</s1><s2>78290 Croissy-sur-Seine</s2><s3>FRA</s3><sZ>5 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>78290 Croissy-sur-Seine</wicri:noRegion><wicri:noRegion>Centre de Recherches de Croissy</wicri:noRegion><wicri:noRegion>78290 Croissy-sur-Seine</wicri:noRegion></affiliation></author><author><name sortKey="Brotchie, J M" sort="Brotchie, J M" uniqKey="Brotchie J" first="J. M." last="Brotchie">J. M. Brotchie</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Toronto Western Research Institute, University Health Network, Toronto Western Hospital</s1><s2>Toronto, Ontario, M5T 2S8</s2><s3>CAN</s3><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto, Ontario, M5T 2S8</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Experimental neurology : (Print)</title><title level="j" type="abbreviated">Exp. neurol. : (Print)</title><idno type="ISSN">0014-4886</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Experimental neurology : (Print)</title><title level="j" type="abbreviated">Exp. neurol. : (Print)</title><idno type="ISSN">0014-4886</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Basal ganglion</term><term>Clinical management</term><term>Comparative study</term><term>D2 Dopamine receptor</term><term>D3 Dopamine receptor</term><term>Dopamine</term><term>Dopamine agonist</term><term>Dopamine antagonist</term><term>Dopamine receptor</term><term>Dyskinesia</term><term>Human</term><term>Levodopa</term><term>Low dose</term><term>Motor control</term><term>Parkinson disease</term><term>Primates</term><term>Ropinirole</term><term>Selectivity</term><term>Treatment</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Parkinson maladie</term><term>Récepteur dopaminergique D3</term><term>Ropinirole</term><term>Dyskinésie</term><term>Lévodopa</term><term>Primates</term><term>Antagoniste dopamine</term><term>Traitement</term><term>Sélectivité</term><term>Etude comparative</term><term>Récepteur dopaminergique D2</term><term>Dose faible</term><term>Récepteur dopaminergique</term><term>Stimulant dopaminergique</term><term>Conduite à tenir</term><term>Homme</term><term>Dopamine</term><term>Noyau gris central</term><term>Contrôle moteur</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">To date, the lack of highly selective antagonists at the dopamine D<sub>3</sub>receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D<sub>3</sub> versus D<sub>2</sub> receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D<sub>3</sub>-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses. S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D<sub>3</sub> receptor stimulation. Indeed, stimulation of D<sub>3</sub> receptors may be detrimental to the anti-parkinsonian properties of D<sub>2</sub>/D<sub>3</sub> agonists. Selectivity for stimulation of D<sub>2</sub>, over D<sub>3</sub>, receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia.</div></front></TEI><affiliations><list><country><li>Canada</li><li>France</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Manchester</li></region><settlement><li>Manchester</li></settlement><orgName><li>Université de Manchester</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Silverdale, M A" sort="Silverdale, M A" uniqKey="Silverdale M" first="M. A." last="Silverdale">M. A. Silverdale</name></region><name sortKey="Crossman, A R" sort="Crossman, A R" uniqKey="Crossman A" first="A. R." last="Crossman">A. R. Crossman</name><name sortKey="Crossman, A R" sort="Crossman, A R" uniqKey="Crossman A" first="A. R." last="Crossman">A. R. Crossman</name><name sortKey="Nicholson, S L" sort="Nicholson, S L" uniqKey="Nicholson S" first="S. L." last="Nicholson">S. L. Nicholson</name><name sortKey="Ravenscroft, P" sort="Ravenscroft, P" uniqKey="Ravenscroft P" first="P." last="Ravenscroft">P. Ravenscroft</name><name sortKey="Ravenscroft, P" sort="Ravenscroft, P" uniqKey="Ravenscroft P" first="P." last="Ravenscroft">P. Ravenscroft</name><name sortKey="Silverdale, M A" sort="Silverdale, M A" uniqKey="Silverdale M" first="M. A." last="Silverdale">M. A. Silverdale</name></country><country name="France"><noRegion><name sortKey="Millan, M J" sort="Millan, M J" uniqKey="Millan M" first="M. J." last="Millan">M. J. Millan</name></noRegion></country><country name="Canada"><noRegion><name sortKey="Brotchie, J M" sort="Brotchie, J M" uniqKey="Brotchie J" first="J. M." last="Brotchie">J. M. 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