Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors

Guigoni, Céline; Aubert, Incarnation; Li, Q.; Gurevich, Vsevolod V.; Benovic, J. L.; Ferry, Sandrine; Mach, Ulrich R.; Stark, Holger; Leriche, Ludovic; Håkansson, Katarina; Bioulac, Bernard; Gross, Christian E.; Sokoloff, Pierre; Fisone, Gilberto; Gurevich, Eugenia V.; Bloch, Bertrand; Bézard, Erwan

doi:10.1016/j.parkreldis.2004.11.005

Cited by 121 publications

(75 citation statements)

References 21 publications

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“…These cells are generally referred to as striatonigral MSNs and are selectively enriched in dopamine D1 receptors (D1Rs) (3). The development of sensitized D1R-mediated transmission in striatonigral MSNs has been proposed to play a critical role in the generation of the motor side effects, or dyskinesia, produced by repeated administration of L-DOPA, the most common antiparkinsonian medication (4,5).…”

Section: Dyskinesia a Motor Complication Caused By Prolonged Adminismentioning

confidence: 99%

Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism

Santini

Feyder

Gangarossa

et al. 2012

Journal of Biological Chemistry

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Background: DARPP-32 is implicated in L-DOPA-induced dyskinesia. Results: PKA-dependent phosphorylation of DARPP-32 in a distinct subset of striatal neurons is required for L-DOPA-induced activation of ERK and mTORC1. Conclusion: PKA-dependent phosphorylation of DARPP-32 plays a critical role in dyskinesia and associated signaling alterations. Significance: The PKA/DARPP-32 cascade is a key target for the treatment of dyskinesia.

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Section: Dyskinesia a Motor Complication Caused By Prolonged Adminismentioning

confidence: 99%

Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism

Santini

Feyder

Gangarossa

et al. 2012

Journal of Biological Chemistry

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“…Neurobiological mechanisms responsible for motor symptoms produced by the degeneration of dopaminergic neurons in PD are poorly understood. It is generally believed that dysregulation of DA receptor signaling in the basal ganglia plays a role in generating motor deficits [30,50,76,96], but the underlying molecular events are not known.…”

Section: Introductionmentioning

confidence: 99%

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Bychkov

Joyce

et al. 2008

Neurobiology of Aging

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Arrestins and G proteins-coupled receptor kinases (GRKs) regulate signaling and trafficking of G protein-coupled receptors. We investigated changes in the expression of arrestins and GRKs in the striatum of patients with Parkinson's disease without (PD) or with dementia (PDD) at post mortem using Western blotting and ribonuclease protection assay. Both PD and PDD groups had similar degree of dopamine depletion in all striatal regions. Arrestin proteins and mRNAs were increased in the PDD group throughout striatum. Protein and mRNA of GRK5, the major subtype in the human striatum, and GRK3 were also upregulated, whereas GRK2 and 6 were mostly unchanged. The PD group had lower concentration of arrestins and GRKs than the PDD group. There was no statistical link between the load of Alzheimer's pathology and the expression of these signaling proteins. Upregulation of arrestins and GRK in PDD may confer resistance to the therapeutic effects of levodopa often observed in these patients. In addition, increased arrestin and GRK concentrations may lead to dementia via perturbation of multiple signaling mechanisms.

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“…These arise from the combined effects of progressive dopaminergic denervation and chronic levodopa therapy (Olanow et al, 2006). Both result in adaptive changes in striatal neurochemistry that, together, are thought to result in motor fluctuations and dyskinesias seen in treated patients (Jenner, 2000;Calon and Di Paolo 2002;Guigoni et al, 2005;Hurley and Jenner 2006;Linazasoro, 2007).…”

Section: Introductionmentioning

confidence: 99%

Motor deficits and altered striatal gene expression in aphakia (ak) mice

et al. 2007

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Like humans with Parkinsons disease (PD), the ak mouse lacks the majority of the substantia nigra pars compacta (SNc) and experiences striatal denervation. The purpose of this study was to test whether motor abnormalities in the ak mouse progress over time, and whether motor function could be associated with temporal alterations in the striatal transcriptome. Ak and wt mice (28 to 180 days old) were tested using paradigms sensitive to nigrostriatal dysfunction. Results were analyzed using a linear mixed model. Ak mice significantly underperformed wt controls in rotarod, balance beam, string test, pole test and cotton shred tests at all ages examined. Motor performance in ak mice remained constant over the first 6 months of life, with the exception of the cotton shred test, in which ak mice exhibited marginal decline in performance. Dorsal striatal semi-quantitative RT-PCR for 19 dopaminergic, cholinergic, glutaminergic and catabolic genes was performed in 1 and 6 month old groups of ak and wt mice. Preproenkephalin levels in ak mice were elevated in both age groups. Drd1, 3 and 4 levels declined over time, in contrast to increasing Drd2 expression. Additional findings included decreased Chrnα6 expression and elevated VGluT1 expression at both time points in ak mice, and elevated AchE expression in young ak mice only. Results confirm that motor ability does not decline significantly for the first 6 months of life in ak mice. Their striatal gene expression patterns are consistent with dopaminergic denervation, and change over time, despite relatively unaltered motor performance.

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Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors

Cited by 121 publications

References 21 publications

Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism

Dopamine- and cAMP-regulated Phosphoprotein of 32-kDa (DARPP-32)-dependent Activation of Extracellular Signal-regulated Kinase (ERK) and Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling in Experimental Parkinsonism

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

Motor deficits and altered striatal gene expression in aphakia (ak) mice

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