D1 receptor blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys
Identifieur interne : 003832 ( Main/Exploration ); précédent : 003831; suivant : 003833D1 receptor blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys
Auteurs : R. Grondin [Canada] ; V. D. Doan ; L. Gregoire ; P. J. BedardSource :
- Neurology [ 0028-3878 ] ; 1999.
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- Pascal (Inist)
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Abstract
Article abstract-Objective. To determine whether dopamine (DA) D1 or DA D2 receptors are associated predominantly with the antiparkinsonian versus the dyskinetic effect of levodopa. Methods: The authors used four L-dopa-primed, dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys to test whether acute and selective blockade of the DA D1 receptor subtype, using SCH 23390 and NNC 01-112, could reduce L-dopa-induced dyskinesias without altering the relief of symptoms. Blockade of DA receptors using sulpiride (D2) and clozapine (D1-D2-like) was studied for comparison. Results: With the notable exception of the lowest dose of clozapine tested, coadministration of DA D1 or D2 antidopaminergic agents with L-dopa reduced the L-dopa-induced dyskinesias but also caused a return of parkinsonian disability. Prolonged latencies from intake of a single oral dose of L-dopa to turning "on," decreased duration of the "on" state, and a complete failure to induce benefit was also observed. Conclusion: Low-dose clozapine could be an effective adjunct to reduce L-dopa-induced dyskinesias without altering the relief of parkinsonian symptoms. Interactions with many neurotransmitter systems may explain the better pharmacologic profile of clozapine, including DA D4 (rather than D1), serotonin, acetylcholine, and noradrenaline. Neither dyskinesias nor antiparkinsonian effects can be ascribed solely to the D2 or D1 receptor. Thus, some cooperation between the two receptors appears necessary for these behavioral effects.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">D<sub>1</sub> receptor blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys</title><author><name sortKey="Grondin, R" sort="Grondin, R" uniqKey="Grondin R" first="R." last="Grondin">R. Grondin</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neuroscience Research Unit, CHUL Research Centre</s1><s2>Ste-Foy (Quebec)</s2><s3>CAN</s3></inist:fA14><country>Canada</country><wicri:noRegion>Ste-Foy (Quebec)</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Medicine, Faculty of Medicine, Laval University</s1><s2>Ste-Foy (Quebec)</s2><s3>CAN</s3></inist:fA14><country>Canada</country><wicri:noRegion>Ste-Foy (Quebec)</wicri:noRegion></affiliation></author><author><name sortKey="Doan, V D" sort="Doan, V D" uniqKey="Doan V" first="V. D." last="Doan">V. D. Doan</name></author><author><name sortKey="Gregoire, L" sort="Gregoire, L" uniqKey="Gregoire L" first="L." last="Gregoire">L. Gregoire</name></author><author><name sortKey="Bedard, P J" sort="Bedard, P J" uniqKey="Bedard P" first="P. J." last="Bedard">P. J. Bedard</name></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">99-0175973</idno><date when="1999">1999</date><idno type="stanalyst">PASCAL 99-0175973 INIST</idno><idno type="RBID">Pascal:99-0175973</idno><idno type="wicri:Area/PascalFrancis/Corpus">000D78</idno><idno type="wicri:Area/PascalFrancis/Curation">001145</idno><idno type="wicri:Area/PascalFrancis/Checkpoint">000C65</idno><idno type="wicri:explorRef" wicri:stream="PascalFrancis" wicri:step="Checkpoint">000C65</idno><idno type="wicri:Area/Main/Merge">003E18</idno><idno type="wicri:Area/Main/Curation">003832</idno><idno type="wicri:Area/Main/Exploration">003832</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">D<sub>1</sub> receptor blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys</title><author><name sortKey="Grondin, R" sort="Grondin, R" uniqKey="Grondin R" first="R." last="Grondin">R. Grondin</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Neuroscience Research Unit, CHUL Research Centre</s1><s2>Ste-Foy (Quebec)</s2><s3>CAN</s3></inist:fA14><country>Canada</country><wicri:noRegion>Ste-Foy (Quebec)</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Medicine, Faculty of Medicine, Laval University</s1><s2>Ste-Foy (Quebec)</s2><s3>CAN</s3></inist:fA14><country>Canada</country><wicri:noRegion>Ste-Foy (Quebec)</wicri:noRegion></affiliation></author><author><name sortKey="Doan, V D" sort="Doan, V D" uniqKey="Doan V" first="V. D." last="Doan">V. D. Doan</name></author><author><name sortKey="Gregoire, L" sort="Gregoire, L" uniqKey="Gregoire L" first="L." last="Gregoire">L. Gregoire</name></author><author><name sortKey="Bedard, P J" sort="Bedard, P J" uniqKey="Bedard P" first="P. J." last="Bedard">P. J. Bedard</name></author></analytic><series><title level="j" type="main">Neurology</title><title level="j" type="abbreviated">Neurology</title><idno type="ISSN">0028-3878</idno><imprint><date when="1999">1999</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Neurology</title><title level="j" type="abbreviated">Neurology</title><idno type="ISSN">0028-3878</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal</term><term>Antiparkinson agent</term><term>Chemotherapy</term><term>D1 Dopamine receptor</term><term>D2 Dopamine receptor</term><term>Dyskinesia</term><term>Levodopa</term><term>Mechanism of action</term><term>Monkey</term><term>Parkinson disease</term><term>Toxicity</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Parkinson maladie</term><term>Dyskinésie</term><term>Lévodopa</term><term>Antiparkinsonien</term><term>Récepteur dopaminergique D2</term><term>Récepteur dopaminergique D1</term><term>Chimiothérapie</term><term>Toxicité</term><term>Animal</term><term>Singe</term><term>Mécanisme action</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Singe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Article abstract-Objective. To determine whether dopamine (DA) D<sub>1</sub> or DA D<sub>2</sub> receptors are associated predominantly with the antiparkinsonian versus the dyskinetic effect of levodopa. Methods: The authors used four L-dopa-primed, dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys to test whether acute and selective blockade of the DA D<sub>1</sub> receptor subtype, using SCH 23390 and NNC 01-112, could reduce L-dopa-induced dyskinesias without altering the relief of symptoms. Blockade of DA receptors using sulpiride (D<sub>2</sub>) and clozapine (D<sub>1</sub>-D<sub>2</sub>-like) was studied for comparison. Results: With the notable exception of the lowest dose of clozapine tested, coadministration of DA D<sub>1</sub> or D<sub>2</sub> antidopaminergic agents with L-dopa reduced the L-dopa-induced dyskinesias but also caused a return of parkinsonian disability. Prolonged latencies from intake of a single oral dose of L-dopa to turning "on," decreased duration of the "on" state, and a complete failure to induce benefit was also observed. Conclusion: Low-dose clozapine could be an effective adjunct to reduce L-dopa-induced dyskinesias without altering the relief of parkinsonian symptoms. Interactions with many neurotransmitter systems may explain the better pharmacologic profile of clozapine, including DA D<sub>4</sub> (rather than D<sub>1</sub>), serotonin, acetylcholine, and noradrenaline. Neither dyskinesias nor antiparkinsonian effects can be ascribed solely to the D<sub>2</sub> or D<sub>1</sub> receptor. Thus, some cooperation between the two receptors appears necessary for these behavioral effects.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Bedard, P J" sort="Bedard, P J" uniqKey="Bedard P" first="P. J." last="Bedard">P. J. Bedard</name><name sortKey="Doan, V D" sort="Doan, V D" uniqKey="Doan V" first="V. D." last="Doan">V. D. Doan</name><name sortKey="Gregoire, L" sort="Gregoire, L" uniqKey="Gregoire L" first="L." last="Gregoire">L. Gregoire</name></noCountry><country name="Canada"><noRegion><name sortKey="Grondin, R" sort="Grondin, R" uniqKey="Grondin R" first="R." last="Grondin">R. Grondin</name></noRegion><name sortKey="Grondin, R" sort="Grondin, R" uniqKey="Grondin R" first="R." last="Grondin">R. Grondin</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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