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 : 006E51 ( Main/Merge ); précédent : 006E50; suivant : 006E52Neural 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.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Singe.
English descriptors
- KwdEn :
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 subcutaneously) or levodopa (8.0 mg/kg orally), 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.
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<author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name>
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<series><title level="j" type="main">Movement disorders</title>
<title level="j" type="abbreviated">Mov. disord.</title>
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<imprint><date when="2001">2001</date>
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<seriesStmt><title level="j" type="main">Movement disorders</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Agonist</term>
<term>Animal</term>
<term>Animal model</term>
<term>Antagonist</term>
<term>Antiparkinson agent</term>
<term>Comparative study</term>
<term>Dopamine receptor</term>
<term>Dyskinesia</term>
<term>Idazoxan</term>
<term>Levodopa</term>
<term>Mechanism of action</term>
<term>Monkey</term>
<term>Parkinson disease</term>
<term>Treatment</term>
<term>α2-Adrenergic receptor</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Parkinson maladie</term>
<term>Idazoxan</term>
<term>Antagoniste</term>
<term>Récepteur α2-adrénergique</term>
<term>Apomorphine</term>
<term>Agoniste</term>
<term>Récepteur dopaminergique</term>
<term>Lévodopa</term>
<term>Antiparkinsonien</term>
<term>Dyskinésie</term>
<term>Modèle animal</term>
<term>Traitement</term>
<term>Mécanisme action</term>
<term>Animal</term>
<term>Singe</term>
<term>Etude comparative</term>
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<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. Alpha<sub>2</sub>
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 subcutaneously) or levodopa (8.0 mg/kg orally), 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 alpha<sub>2</sub>
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.</div>
</front>
</TEI>
<affiliations><list><country><li>Royaume-Uni</li>
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<li>Grand Manchester</li>
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<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="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>
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</record>
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