Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys.
Identifieur interne : 000946 ( PubMed/Checkpoint ); précédent : 000945; suivant : 000947Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys.
Auteurs : Nicolas Morin [Canada] ; Marc Morissette ; Laurent Grégoire ; Baltazar Gomez-Mancilla ; Fabrizio Gasparini ; Thérèse Di PaoloSource :
- Neuropharmacology [ 1873-7064 ] ; 2013.
English descriptors
- KwdEn :
- 2-Amino-5-phosphonovalerate (analogs & derivatives), Amino Acids, Animals, Basal Ganglia (drug effects), Basal Ganglia (metabolism), Corpus Striatum (drug effects), Corpus Striatum (metabolism), Dyskinesia, Drug-Induced (prevention & control), Female, Imidazoles, Levodopa (adverse effects), Macaca fascicularis, Oximes, Parkinsonian Disorders (drug therapy), Parkinsonian Disorders (metabolism), Phenols, Piperidines, Pyridines (pharmacology), Pyridines (therapeutic use), Quinazolines, Radioligand Assay, Receptor, Metabotropic Glutamate 5 (antagonists & inhibitors), Receptor, Metabotropic Glutamate 5 (metabolism), Receptors, AMPA (metabolism), Receptors, N-Methyl-D-Aspartate (metabolism), Tritium, Xanthenes.
- MESH :
- chemical , adverse effects : Levodopa.
- chemical , analogs & derivatives : 2-Amino-5-phosphonovalerate.
- chemical , antagonists & inhibitors : Receptor, Metabotropic Glutamate 5.
- chemical , metabolism : Receptor, Metabotropic Glutamate 5, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate.
- chemical , pharmacology : Pyridines.
- chemical , therapeutic use : Pyridines.
- chemical : Amino Acids, Imidazoles, Oximes, Phenols, Piperidines, Quinazolines, Tritium, Xanthenes.
- drug effects : Basal Ganglia, Corpus Striatum.
- drug therapy : Parkinsonian Disorders.
- metabolism : Basal Ganglia, Corpus Striatum, Parkinsonian Disorders.
- prevention & control : Dyskinesia, Drug-Induced.
- Animals, Female, Macaca fascicularis, Radioligand Assay.
Abstract
Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed dyskinesias while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in L-DOPA-treated MPTP monkeys compared to controls but not in those treated with L-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (B(max)) of [(3)H]ABP688 specific binding increased in L-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in L-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in L-DOPA-treated MPTP monkeys compared to controls, saline and L-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.
DOI: 10.1016/j.neuropharm.2013.05.028
PubMed: 23756168
Affiliations:
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pubmed:23756168Le document en format XML
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<front><div type="abstract" xml:lang="en">Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed dyskinesias while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in L-DOPA-treated MPTP monkeys compared to controls but not in those treated with L-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (B(max)) of [(3)H]ABP688 specific binding increased in L-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in L-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in L-DOPA-treated MPTP monkeys compared to controls, saline and L-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.</div>
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<Abstract><AbstractText>Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed dyskinesias while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in L-DOPA-treated MPTP monkeys compared to controls but not in those treated with L-DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (B(max)) of [(3)H]ABP688 specific binding increased in L-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in L-DOPA-treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in L-DOPA-treated MPTP monkeys compared to controls, saline and L-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission.</AbstractText>
<CopyrightInformation>Copyright © 2013 Elsevier Ltd. All rights reserved.</CopyrightInformation>
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</MeshHeadingList>
<KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine</Keyword>
<Keyword MajorTopicYN="N">2-methyl-6-(phenylethynyl)pyridine</Keyword>
<Keyword MajorTopicYN="N">3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine</Keyword>
<Keyword MajorTopicYN="N">6-OHDA</Keyword>
<Keyword MajorTopicYN="N">6-hydroxydopamine</Keyword>
<Keyword MajorTopicYN="N">AMPA</Keyword>
<Keyword MajorTopicYN="N">AMPA receptor</Keyword>
<Keyword MajorTopicYN="N">B(max)</Keyword>
<Keyword MajorTopicYN="N">DA</Keyword>
<Keyword MajorTopicYN="N">DL</Keyword>
<Keyword MajorTopicYN="N">DM</Keyword>
<Keyword MajorTopicYN="N">GP</Keyword>
<Keyword MajorTopicYN="N">GPe</Keyword>
<Keyword MajorTopicYN="N">GPi</Keyword>
<Keyword MajorTopicYN="N">K(d)</Keyword>
<Keyword MajorTopicYN="N">LID</Keyword>
<Keyword MajorTopicYN="N">MPEP</Keyword>
<Keyword MajorTopicYN="N">MPTP</Keyword>
<Keyword MajorTopicYN="N">MTEP</Keyword>
<Keyword MajorTopicYN="N">N-methyl-d-aspartate</Keyword>
<Keyword MajorTopicYN="N">NMDA</Keyword>
<Keyword MajorTopicYN="N">NMDA receptor</Keyword>
<Keyword MajorTopicYN="N">PD</Keyword>
<Keyword MajorTopicYN="N">Parkinson's disease</Keyword>
<Keyword MajorTopicYN="N">VL</Keyword>
<Keyword MajorTopicYN="N">VM</Keyword>
<Keyword MajorTopicYN="N">affinity</Keyword>
<Keyword MajorTopicYN="N">density</Keyword>
<Keyword MajorTopicYN="N">dopamine</Keyword>
<Keyword MajorTopicYN="N">dorsolateral</Keyword>
<Keyword MajorTopicYN="N">dorsomedial</Keyword>
<Keyword MajorTopicYN="N">external globus pallidus</Keyword>
<Keyword MajorTopicYN="N">globus pallidus</Keyword>
<Keyword MajorTopicYN="N">internal globus pallidus</Keyword>
<Keyword MajorTopicYN="N">l-3,4-dihydroxyphenylalanine</Keyword>
<Keyword MajorTopicYN="N">l-DOPA</Keyword>
<Keyword MajorTopicYN="N">l-DOPA-induced dyskinesias</Keyword>
<Keyword MajorTopicYN="N">mGlu</Keyword>
<Keyword MajorTopicYN="N">mGlu2/3 receptor</Keyword>
<Keyword MajorTopicYN="N">mGlu5 receptor</Keyword>
<Keyword MajorTopicYN="N">metabotropic glutamate</Keyword>
<Keyword MajorTopicYN="N">ventrolateral</Keyword>
<Keyword MajorTopicYN="N">ventromedial</Keyword>
<Keyword MajorTopicYN="N">α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="received"><Year>2012</Year>
<Month>10</Month>
<Day>29</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised"><Year>2013</Year>
<Month>05</Month>
<Day>17</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted"><Year>2013</Year>
<Month>05</Month>
<Day>18</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2013</Year>
<Month>6</Month>
<Day>13</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed"><Year>2013</Year>
<Month>6</Month>
<Day>13</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2014</Year>
<Month>8</Month>
<Day>15</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">23756168</ArticleId>
<ArticleId IdType="pii">S0028-3908(13)00242-6</ArticleId>
<ArticleId IdType="doi">10.1016/j.neuropharm.2013.05.028</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>Canada</li>
</country>
</list>
<tree><noCountry><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</name>
<name sortKey="Gasparini, Fabrizio" sort="Gasparini, Fabrizio" uniqKey="Gasparini F" first="Fabrizio" last="Gasparini">Fabrizio Gasparini</name>
<name sortKey="Gomez Mancilla, Baltazar" sort="Gomez Mancilla, Baltazar" uniqKey="Gomez Mancilla B" first="Baltazar" last="Gomez-Mancilla">Baltazar Gomez-Mancilla</name>
<name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Grégoire">Laurent Grégoire</name>
<name sortKey="Morissette, Marc" sort="Morissette, Marc" uniqKey="Morissette M" first="Marc" last="Morissette">Marc Morissette</name>
</noCountry>
<country name="Canada"><noRegion><name sortKey="Morin, Nicolas" sort="Morin, Nicolas" uniqKey="Morin N" first="Nicolas" last="Morin">Nicolas Morin</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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