ParkinsonCanadaV1, Main, Exploration, bibRecord, 001038

The effects of fast-off-D2 receptor antagonism on L-DOPA-induced dyskinesia and psychosis in parkinsonian macaques

Identifieur interne : 001038 ( Main/Exploration ); précédent : 001037; suivant : 001039

The effects of fast-off-D2 receptor antagonism on L-DOPA-induced dyskinesia and psychosis in parkinsonian macaques

Auteurs : James B. Koprich [Canada] ; Philippe Huot [Canada] ; Susan H. Fox [Canada] ; Keith Jarvie [Canada] ; Anthony E. Lang [Canada] ; Philip Seeman [Canada] ; Jonathan M. Brotchie [Canada]

Source :

Progress in neuro-psychopharmacology & biological psychiatry [ 0278-5846 ] ; 2013.

RBID : Pascal:13-0159777

Descripteurs français

Pascal (Inist)
- Récepteur dopaminergique D2, Lévodopa, Dyskinésie, Psychose, Maladie de Parkinson, Singe, Neuroleptique, Antipsychotique, Traitement, Animal, Toxicité, Complication, Antiparkinsonien, Psychotrope, Contrôle moteur.
Wicri :
- topic : Singe.

English descriptors

KwdEn :
- Animal, Antiparkinson agent, Antipsychotic, Complication, D2 Dopamine receptor, Dyskinesia, Levodopa, Monkey, Motor control, Neuroleptic, Parkinson disease, Psychosis, Psychotropic, Toxicity, Treatment.

Abstract

3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38 min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23 s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100 mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100 mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.

Affiliations:

Canada

Links toward previous steps (curation, corpus...)

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Le document en format XML

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<term>Dyskinesia</term>
<term>Levodopa</term>
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<term>Neuroleptic</term>
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<front><div type="abstract" xml:lang="en">3,4-Dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) is compromised by motor side effects, such as dyskinesia and non-motor problems, including psychosis. Because of the marked reduction in brain dopamine in PD and the resultant dopamine D2 receptor supersensitivity, it is impossible to use standard potent dopamine D2 receptor antagonists such as haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of L-DOPA. Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38 min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2 drug, CLR151 (50% dissociation at 23 s) to modify L-DOPA actions in cynomolgus macaques with MPTP-parkinsonism. CLR151 (100 mg/kg p.o.) reduced L-DOPA-induced dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action. CLR151 (100 mg/kg) also reduced psychosis-like behaviour (i.e. reduced apparent visual hallucinations by 78%). Nevertheless, this dose of CLR151 significantly reduced the duration of anti-parkinsonian action of L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2 dopamine receptor antagonists, with D2-off-rate values close to those for CLR151, are unlikely to be useful in the treatment of dyskinesia and psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.</div>
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	La maladie de Parkinson au Canada (serveur d'exploration)
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La maladie de Parkinson au Canada (serveur d'exploration)

The effects of fast-off-D2 receptor antagonism on L-DOPA-induced dyskinesia and psychosis in parkinsonian macaques

The effects of fast-off-D2 receptor antagonism on L-DOPA-induced dyskinesia and psychosis in parkinsonian macaques

Source :

Descripteurs français

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