Contribution of brain serotonin subtype 1B receptors in levodopa-induced motor complications.
Identifieur interne : 000786 ( Main/Exploration ); précédent : 000785; suivant : 000787Contribution of brain serotonin subtype 1B receptors in levodopa-induced motor complications.
Auteurs : Nicolas Morin [Canada] ; Marc Morissette [Canada] ; Laurent Grégoire [Canada] ; Alex Rajput [Canada] ; Ali H. Rajput [Canada] ; Thérèse Di Paolo [Canada]Source :
- Neuropharmacology [ 1873-7064 ] ; 2015.
English descriptors
- KwdEn :
- Aged, Aged, 80 and over, Animals, Antiparkinson Agents (pharmacology), Antiparkinson Agents (toxicity), Brain (drug effects), Brain (metabolism), Dyskinesia, Drug-Induced (metabolism), Excitatory Amino Acid Antagonists (pharmacology), Female, Humans, Levodopa (pharmacology), Levodopa (toxicity), MPTP Poisoning (drug therapy), MPTP Poisoning (metabolism), Macaca fascicularis, Male, Ovariectomy, Parkinson Disease (drug therapy), Parkinson Disease (metabolism), Pyridines (pharmacology), Receptor, Metabotropic Glutamate 5 (antagonists & inhibitors), Receptor, Metabotropic Glutamate 5 (metabolism), Receptor, Serotonin, 5-HT1B (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Receptor, Metabotropic Glutamate 5.
- chemical , metabolism : Receptor, Metabotropic Glutamate 5, Receptor, Serotonin, 5-HT1B.
- chemical , pharmacology : Antiparkinson Agents, Excitatory Amino Acid Antagonists, Levodopa, Pyridines.
- chemical , toxicity : Antiparkinson Agents, Levodopa.
- drug effects : Brain.
- drug therapy : MPTP Poisoning, Parkinson Disease.
- metabolism : Brain, Dyskinesia, Drug-Induced, MPTP Poisoning, Parkinson Disease.
- Aged, Aged, 80 and over, Animals, Female, Humans, Macaca fascicularis, Male, Ovariectomy.
Abstract
L-DOPA-induced dyskinesias (LID) are abnormal involuntary movements limiting the chronic use of L-DOPA, the main pharmacological treatment of Parkinson's disease. Serotonin receptors are implicated in the development of LID and modulation of basal ganglia 5-HT1B receptors is a potential therapeutic alternative in Parkinson's disease. In the present study, we used receptor-binding autoradiography of the 5-HT1B-selective radioligand [3H]GR125743 to investigate possible contributions of changes in ligand binding of this receptor in LID in post-mortem brain specimens from Parkinson's disease patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist and has been shown to reduce the development of LID in these monkeys in a chronic treatment of one month. [3H]GR125743 specific binding to striatal and pallidal 5-HT1B receptors respectively were only increased in L-DOPA-treated MPTP monkeys (dyskinetic monkeys) as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesias scores correlated positively with this binding. Parkinson's disease patients with motor complications (L-DOPA-induced dyskinesias and wearing-off) had higher [3H]GR125743 specific binding compared to those without motor complications and controls in the basal ganglia. Reduction of motor complications was associated with normal striatal 5-HT1B receptors, suggesting the potential of this receptor for the management of motor complications in Parkinson's disease.
DOI: 10.1016/j.neuropharm.2015.08.002
PubMed: 26254863
Affiliations:
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Electronic address: nicolas.morin.4@ulaval.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Faculty of Pharmacy, Université Laval, Quebec City, G1K 7P4, Canada; Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City, G1V 4G2</wicri:regionArea><wicri:noRegion>G1V 4G2</wicri:noRegion></affiliation></author><author><name sortKey="Morissette, Marc" sort="Morissette, Marc" uniqKey="Morissette M" first="Marc" last="Morissette">Marc Morissette</name><affiliation wicri:level="1"><nlm:affiliation>Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City, G1V 4G2, Canada. 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Rajput</name><affiliation wicri:level="1"><nlm:affiliation>Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada. Electronic address: Ali.Rajput@saskatoonhealthregion.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8</wicri:regionArea><wicri:noRegion>S7N 0W8</wicri:noRegion></affiliation></author><author><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</name><affiliation wicri:level="1"><nlm:affiliation>Faculty of Pharmacy, Université Laval, Quebec City, G1K 7P4, Canada; Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City, G1V 4G2, Canada. Electronic address: therese.dipaolo@crchul.ulaval.ca.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Faculty of Pharmacy, Université Laval, Quebec City, G1K 7P4, Canada; Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City, G1V 4G2</wicri:regionArea><wicri:noRegion>G1V 4G2</wicri:noRegion></affiliation></author></analytic><series><title level="j">Neuropharmacology</title><idno type="eISSN">1873-7064</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Animals</term><term>Antiparkinson Agents (pharmacology)</term><term>Antiparkinson Agents (toxicity)</term><term>Brain (drug effects)</term><term>Brain (metabolism)</term><term>Dyskinesia, Drug-Induced (metabolism)</term><term>Excitatory Amino Acid Antagonists (pharmacology)</term><term>Female</term><term>Humans</term><term>Levodopa (pharmacology)</term><term>Levodopa (toxicity)</term><term>MPTP Poisoning (drug therapy)</term><term>MPTP Poisoning (metabolism)</term><term>Macaca fascicularis</term><term>Male</term><term>Ovariectomy</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (metabolism)</term><term>Pyridines (pharmacology)</term><term>Receptor, Metabotropic Glutamate 5 (antagonists & inhibitors)</term><term>Receptor, Metabotropic Glutamate 5 (metabolism)</term><term>Receptor, Serotonin, 5-HT1B (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Receptor, Metabotropic Glutamate 5</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Receptor, Metabotropic Glutamate 5</term><term>Receptor, Serotonin, 5-HT1B</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiparkinson Agents</term><term>Excitatory Amino Acid Antagonists</term><term>Levodopa</term><term>Pyridines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Antiparkinson Agents</term><term>Levodopa</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Brain</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>MPTP Poisoning</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Brain</term><term>Dyskinesia, Drug-Induced</term><term>MPTP Poisoning</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Aged</term><term>Aged, 80 and over</term><term>Animals</term><term>Female</term><term>Humans</term><term>Macaca fascicularis</term><term>Male</term><term>Ovariectomy</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">L-DOPA-induced dyskinesias (LID) are abnormal involuntary movements limiting the chronic use of L-DOPA, the main pharmacological treatment of Parkinson's disease. Serotonin receptors are implicated in the development of LID and modulation of basal ganglia 5-HT1B receptors is a potential therapeutic alternative in Parkinson's disease. In the present study, we used receptor-binding autoradiography of the 5-HT1B-selective radioligand [3H]GR125743 to investigate possible contributions of changes in ligand binding of this receptor in LID in post-mortem brain specimens from Parkinson's disease patients (n=14) and control subjects (n=11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n=5), L-DOPA (n=4) or L-DOPA+2-methyl-6-(phenylethynyl)pyridine (MPEP) (n=5), and control monkeys (n=4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist and has been shown to reduce the development of LID in these monkeys in a chronic treatment of one month. [3H]GR125743 specific binding to striatal and pallidal 5-HT1B receptors respectively were only increased in L-DOPA-treated MPTP monkeys (dyskinetic monkeys) as compared to controls, saline and L-DOPA+MPEP MPTP monkeys; dyskinesias scores correlated positively with this binding. Parkinson's disease patients with motor complications (L-DOPA-induced dyskinesias and wearing-off) had higher [3H]GR125743 specific binding compared to those without motor complications and controls in the basal ganglia. Reduction of motor complications was associated with normal striatal 5-HT1B receptors, suggesting the potential of this receptor for the management of motor complications in Parkinson's disease.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Morin, Nicolas" sort="Morin, Nicolas" uniqKey="Morin N" first="Nicolas" last="Morin">Nicolas Morin</name></noRegion><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</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><name sortKey="Rajput, Alex" sort="Rajput, Alex" uniqKey="Rajput A" first="Alex" last="Rajput">Alex Rajput</name><name sortKey="Rajput, Ali H" sort="Rajput, Ali H" uniqKey="Rajput A" first="Ali H" last="Rajput">Ali H. 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