Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

Bézard, Erwan; Ferry, Sandrine; Mach, Ulrich R.; Stark, Holger; Leriche, Ludovic; Boraud, Thomas; Gross, Christian E.; Sokoloff, Pierre

doi:10.1038/nm875

Cited by 364 publications

(339 citation statements)

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“…The relationship between DRD3 and motor control is supported by the finding that DRD3 overexpression produces in nonhuman primates levodopa-induced dyskinesia (14). Although DRD3 receptor overexpression in the basal ganglia has been implicated in levodopa-induced dyskinesia, abnormalities in the cerebellar DRD3 receptors could be responsible for ET.…”

Section: Discussionmentioning

confidence: 92%

“…Linkage in the presence of association was positively demonstrated by the use of the Transmission Disequilibrium Test (TDT) in families with both parents available and at least one heterozygous parent (families 2,9,12,14,19,21) or the Sib-TDT (S-TDT) in other informative sibships (families 7,8,15,17,18,25,26,28,30) (18). TDT 2 value was 7.364 (P ϭ 0.0067), and S-TDT zЈ score was 4.306 (P Ͻ 0.00001).…”

Section: Resultsmentioning

confidence: 99%

“…Although dopaminergic drugs are ineffective in ET, olanzapine and clozapine, which are nonselective dopamine D2-like receptor blockers (acting at both DRD2 and DRD3 receptors), have been found to improve ET (32,33). Therefore, we propose DRD3-selective partial agonists or antagonists (14,34) as a possible pharmacotherapy of ET.…”

Section: Discussionmentioning

confidence: 98%

“…DRD3 expression is reduced in Parkinson's disease (PD) (13), and a study in a monkey model of PD indicates that DRD3 hyperfunction is responsible for dyskinesia, a motor complication of PD treatment (14). Largest DRD3 densities occur in the basal ganglia, but cerebellum also expresses DRD3 at a lower density (15).…”

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confidence: 99%

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A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Jeanneteau

Funalot

Jankovic

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Familial essential tremor (ET), the most common inherited movement disorder, is generally transmitted as an autosomal dominant trait. A genome-wide scan for ET revealed one major locus on chromosome 3q13. Here, we report that the Ser9Gly variant in the dopamine D 3 receptor gene (DRD3), localized on 3q13.3, is associated and cosegregates with familial ET in 23 out of 30 French families. Sequencing revealed no other nonsynonymous variants in the DRD3-coding sequence and in the first 871 bp of the 5 flanking region. Moreover, Gly-9 homozygous patients presented with more severe and͞or earlier onset forms of the disease than heterozygotes. A replication study comparing 276 patients with ET and 184 normal controls confirmed the association of the Gly-9 variant with risk and age-at-onset of ET. In human embryonic kidney (HEK) 293-transfected cells, the Gly-9 variant did not differ from the Ser-9 variant with respect to glycosylation and to anterograde and retrograde trafficking, but dopamine had an affinity that was four to five times higher. With the Gly-9 variant, the dopamine-mediated cAMP response was increased, and the mitogen-associated protein kinase (MAPK) signal was prolonged, as compared with the Ser-9 variant. The gain-of-function produced by the Gly-9 variant may explain why drugs active against tremor in Parkinson's disease (PD) are usually not effective in the treatment of ET and suggests that DRD3 partial agonists or antagonists should be considered as novel therapeutic options for patients with ET.dopamine receptor ͉ gain-of-function ͉ gene dosage ͉ movement disorder ͉ polymorphism

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Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

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A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Jeanneteau

Funalot

Jankovic

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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175

120

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“…8 Among multiple receptor subtypes, D 3 receptors have been proposed as putative targets for atypical antipsychotic drugs, and thus, some works suggest that D 3 antagonism may cause cognitive enhancement 9 and a lack of catalepsy. 10 In an attempt to prove these hypotheses, an intensive effort has been directed toward the development of selective ligands for dopamine D 3 receptors. 11 Some of these D 3 ligands are now in ongoing clinical development as potential therapeutics for the aforementioned disorders.…”

mentioning

confidence: 99%

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

Ortega

Raviña

Masaguer

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c tA series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D 1 , D 2 , and D 3 receptors. Some of these compounds showed high D 2 and/or D 3 affinity and selectivity over the D 1 receptor. The SAR study of these compounds revealed structural characteristics that decisively influenced their D 2 and D 3 affinities. Structural models of the complexes between some of the most representative compounds of this series and the D 2 and D 3 receptors were obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds showed moderate binding affinity on 5-HT 2A which could contribute to reducing the occurrence of extrapyramidal side effects as potential antipsychotics.Ó 2009 Elsevier Ltd. All rights reserved.Dopamine (DA) is a major neurotransmitter in the central nervous system (CNS) that plays important roles in behaviour and cognition, ranging from movement to emotion, sensitization to addiction, and development to plasticity. All DA receptors belong to a superfamily of large peptides that are coupled to G-proteins and modified by attached carbohydrate, lipid-ester or phosphate groups. They are characterized by having seven hydrophobic transmembrane-spanning regions, as well as a functionally critical third intracytoplasmic loop that interacts with G-proteins and other effector molecules to mediate the physiological and neurochemical effects of the receptors. Based on their pharmacological profiles, including their effects on different signal transduction cascades, these receptors are currently divided into two families: the D 1 -like family or adenylyl-cyclase stimulators, which includes D 1 and D 5 receptors, and the D 2 -like family or adenylyl-cyclase inhibitors, which includes D 2 , D 3 and D 4 receptors. 1 The D 3 dopamine receptor was first identified and clonated by Sokoloff et al. 2 in 1990 and has been shown to be an interesting target for different CNS diseases. Although its structure and pharmacology are very similar to dopamine D 2 , the D 3 receptor is generally less abundant than the D 2 receptor, and the difference is particularly striking in the caudate putamen, where D 2 receptors are densest and D 3 receptors are poorly represented. 3 Moreover, D 3 -binding sites and mRNA encoding D 3 receptors are concentrated in the limbic brain areas known to be associated with cognitive and emotional functions. 4 Due to this, the D 3 receptor has been suggested to be a potential target in the treatment of neurological disorders such as schizophrenia, and drug abuse. 5 In schizophrenia, a blockade of D 2 receptors has been considered to be the main mechanism responsible for the efficacy of antipsychotics, 6 but the complex profiles of some atypical drugs challenged this assumption, that is, clozapine exhibits activity at multiple receptors. 7 Now there is an increasing body of clinical evidence that supports the notion that multi-target ligands may be more efficacious than strictly selective ...

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Medication-Related Impulse Control and Repetitive Behaviors in Parkinson Disease

Voon¹,

Fox²

2007

Arch Neurol

387

357

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range of behaviors presumed to be related to aberrant or excessive dopaminergic medications are being increasingly recognized in Parkinson disease. These behaviors are linked by their incentive-or reward-based and repetitive natures and include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, hobbyism, and compulsive medication use. Such behaviors can have potentially devastating psychosocial consequences and are often hidden. Whether these behaviors are simply related to dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson disease play a role is not known. We reviewed the literature on these behaviors in Parkinson disease, including definitions, epidemiological and potential pathophysiological features, and management. The study of these behaviors allows not only improved clinical management but also greater insight into a biologically mediated complex behavioral model.

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Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

Cited by 364 publications

References 29 publications

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

Medication-Related Impulse Control and Repetitive Behaviors in Parkinson Disease

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Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function

Cited by 364 publications

References 29 publications

A functional variant of the dopamine D 3 receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D 3 receptor is associated with risk and age-at-onset of essential tremor

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

Medication-Related Impulse Control and Repetitive Behaviors in Parkinson Disease

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A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor

A functional variant of the dopamine D ₃ receptor is associated with risk and age-at-onset of essential tremor