Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys.
Identifieur interne : 000E29 ( Main/Exploration ); précédent : 000E28; suivant : 000E30Chronic 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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Le document en format XML
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Paolo">Thérèse Di Paolo</name></author></analytic><series><title level="j">Neuropharmacology</title><idno type="eISSN">1873-7064</idno><imprint><date when="2013" type="published">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>2-Amino-5-phosphonovalerate (analogs & derivatives)</term><term>Amino Acids</term><term>Animals</term><term>Basal Ganglia (drug effects)</term><term>Basal Ganglia (metabolism)</term><term>Corpus Striatum (drug effects)</term><term>Corpus Striatum (metabolism)</term><term>Dyskinesia, Drug-Induced (prevention & control)</term><term>Female</term><term>Imidazoles</term><term>Levodopa (adverse effects)</term><term>Macaca fascicularis</term><term>Oximes</term><term>Parkinsonian Disorders (drug therapy)</term><term>Parkinsonian Disorders (metabolism)</term><term>Phenols</term><term>Piperidines</term><term>Pyridines (pharmacology)</term><term>Pyridines (therapeutic 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xml:lang="en"><term>Animals</term><term>Female</term><term>Macaca fascicularis</term><term>Radioligand Assay</term></keywords></textClass></profileDesc></teiHeader><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></front></TEI><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>Pour manipuler ce document sous Unix (Dilib)
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