Neural mechanisms underlying peak‐dose dyskinesia induced by levodopa and apomorphine are distinct: Evidence from the effects of the alpha2 adrenoceptor antagonist idazoxan
Identifieur interne : 004745 ( Main/Exploration ); précédent : 004744; suivant : 004746Neural mechanisms underlying peak‐dose dyskinesia induced by levodopa and apomorphine are distinct: Evidence from the effects of the alpha2 adrenoceptor antagonist idazoxan
Auteurs : Susan H. Fox [Royaume-Uni] ; Brian Henry [Royaume-Uni] ; Micheal P. Hill [Royaume-Uni] ; David Peggs [Royaume-Uni] ; Alan R. Crossman [Royaume-Uni] ; Jonathan M. Brotchie [Royaume-Uni]Source :
- Movement Disorders [ 0885-3185 ] ; 2001-07.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Singe.
English descriptors
- KwdEn :
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset, Adrenergic alpha-Antagonists (pharmacology), Agonist, Animal, Animal model, Animals, Antagonist, Antiparkinson Agents (toxicity), Antiparkinson agent, Apomorphine (toxicity), Callithrix, Comparative study, Corpus Striatum (drug effects), Dopamine receptor, Dose-Response Relationship, Drug, Dyskinesia, Dyskinesia, Drug-Induced (physiopathology), Female, Globus Pallidus (drug effects), Idazoxan, Idazoxan (pharmacology), Levodopa, Levodopa (toxicity), Male, Mechanism of action, Monkey, Neurologic Examination (drug effects), Neurons (drug effects), Norepinephrine (metabolism), Parkinson disease, Parkinson's disease, Substantia Nigra (drug effects), Treatment, alpha2 adrenergic receptor antagonists, apomorphine, dyskinesia, idazoxan, α2-Adrenergic receptor.
- MESH :
- chemical , metabolism : Norepinephrine.
- chemical , pharmacology : Adrenergic alpha-Antagonists, Idazoxan.
- chemical , toxicity : Antiparkinson Agents, Apomorphine, Levodopa.
- chemical : 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
- drug effects : Corpus Striatum, Globus Pallidus, Neurologic Examination, Neurons, Substantia Nigra.
- physiopathology : Dyskinesia, Drug-Induced.
- Animals, Callithrix, Dose-Response Relationship, Drug, Female, Male.
Abstract
Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinson's disease. Alpha2 adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa‐induced dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned, nonhuman primate model of Parkinson's disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine‐induced dyskinesia. MPTP‐lesioned marmosets with stable dyskinesia induced by prolonged levodopa therapy were given an acute challenge with apomorphine (0.3 mg/kg s.c.) or levodopa (8.0 mg/kg p.o.), these doses produced equivalent peak‐dose dyskinesia. Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either apomorphine or levodopa. Idazoxan abolished levodopa‐induced dyskinesia but did not affect apomorphine‐induced dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test). Idazoxan also extended the anti‐parkinsonian actions of levodopa but did not affect those of apomorphine. The pharmacological characteristics of the neural mechanisms underlying levodopa‐induced dyskinesia and apomorphine‐induced dyskinesia in parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha2 adrenoceptors. Specifically, levodopa, but not apomorphine‐induced dyskinesia, involves activation of adrenoceptors. This finding may have major implications for understanding dyskinesia and should be borne in mind when designing clinical studies in which levodopa or dopamine receptor agonist challenges are employed to assess potential anti‐dyskinetic properties of drugs. © 2001 Movement Disorder Society.
Url:
DOI: 10.1002/mds.1148
Affiliations:
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Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="2001-07">2001-07</date><biblScope unit="vol">16</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="642">642</biblScope><biblScope unit="page" to="650">650</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">3CEEEDED227FBE537DA4309A15DCC2F1AE93E369</idno><idno type="DOI">10.1002/mds.1148</idno><idno type="ArticleID">MDS1148</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term><term>1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset</term><term>Adrenergic alpha-Antagonists (pharmacology)</term><term>Agonist</term><term>Animal</term><term>Animal model</term><term>Animals</term><term>Antagonist</term><term>Antiparkinson Agents (toxicity)</term><term>Antiparkinson agent</term><term>Apomorphine (toxicity)</term><term>Callithrix</term><term>Comparative study</term><term>Corpus Striatum (drug effects)</term><term>Dopamine receptor</term><term>Dose-Response Relationship, Drug</term><term>Dyskinesia</term><term>Dyskinesia, Drug-Induced (physiopathology)</term><term>Female</term><term>Globus Pallidus (drug effects)</term><term>Idazoxan</term><term>Idazoxan (pharmacology)</term><term>Levodopa</term><term>Levodopa (toxicity)</term><term>Male</term><term>Mechanism of action</term><term>Monkey</term><term>Neurologic Examination (drug effects)</term><term>Neurons (drug effects)</term><term>Norepinephrine (metabolism)</term><term>Parkinson disease</term><term>Parkinson's disease</term><term>Substantia Nigra (drug effects)</term><term>Treatment</term><term>alpha2 adrenergic receptor antagonists</term><term>apomorphine</term><term>dyskinesia</term><term>idazoxan</term><term>α2-Adrenergic receptor</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Norepinephrine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adrenergic alpha-Antagonists</term><term>Idazoxan</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Antiparkinson Agents</term><term>Apomorphine</term><term>Levodopa</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Corpus Striatum</term><term>Globus Pallidus</term><term>Neurologic Examination</term><term>Neurons</term><term>Substantia Nigra</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Callithrix</term><term>Dose-Response Relationship, Drug</term><term>Female</term><term>Male</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Agoniste</term><term>Animal</term><term>Antagoniste</term><term>Antiparkinsonien</term><term>Apomorphine</term><term>Dyskinésie</term><term>Etude comparative</term><term>Idazoxan</term><term>Lévodopa</term><term>Modèle animal</term><term>Mécanisme action</term><term>Parkinson maladie</term><term>Récepteur dopaminergique</term><term>Récepteur α2-adrénergique</term><term>Singe</term><term>Traitement</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Singe</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinson's disease. Alpha2 adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa‐induced dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned, nonhuman primate model of Parkinson's disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine‐induced dyskinesia. MPTP‐lesioned marmosets with stable dyskinesia induced by prolonged levodopa therapy were given an acute challenge with apomorphine (0.3 mg/kg s.c.) or levodopa (8.0 mg/kg p.o.), these doses produced equivalent peak‐dose dyskinesia. Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either apomorphine or levodopa. Idazoxan abolished levodopa‐induced dyskinesia but did not affect apomorphine‐induced dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test). Idazoxan also extended the anti‐parkinsonian actions of levodopa but did not affect those of apomorphine. The pharmacological characteristics of the neural mechanisms underlying levodopa‐induced dyskinesia and apomorphine‐induced dyskinesia in parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha2 adrenoceptors. Specifically, levodopa, but not apomorphine‐induced dyskinesia, involves activation of adrenoceptors. This finding may have major implications for understanding dyskinesia and should be borne in mind when designing clinical studies in which levodopa or dopamine receptor agonist challenges are employed to assess potential anti‐dyskinetic properties of drugs. © 2001 Movement Disorder Society.</div></front></TEI><affiliations><list><country><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"><noRegion><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name></noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Crossman, Alan R" sort="Crossman, Alan R" uniqKey="Crossman A" first="Alan R." last="Crossman">Alan R. Crossman</name><name sortKey="Henry, Brian" sort="Henry, Brian" uniqKey="Henry B" first="Brian" last="Henry">Brian Henry</name><name sortKey="Henry, Brian" sort="Henry, Brian" uniqKey="Henry B" first="Brian" last="Henry">Brian Henry</name><name sortKey="Hill, Micheal P" sort="Hill, Micheal P" uniqKey="Hill M" first="Micheal P." last="Hill">Micheal P. Hill</name><name sortKey="Peggs, David" sort="Peggs, David" uniqKey="Peggs D" first="David" last="Peggs">David Peggs</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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