Genetic suppression of the dopamine D3 receptor in striatal D1 cells reduces the development of L-DOPA-induced dyskinesia

Lanza, Kathryn; Centner, Ashley; Coyle, Michael; Priore, Isabella Del; Manfredsson, Fredric P.; Bishop, Christopher

doi:10.1016/j.expneurol.2020.113534

Cited by 16 publications

(10 citation statements)

References 41 publications

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“…40 Interestingly, D3 overactivation seems to be functionally related to D1 pathway modification, 39 and recent evidence suggests that aberrant D1-D3 receptor interactions may also contribute to LID. 41 Concerning the alterations in corticostriatal synaptic plasticity, evidence from animal studies suggests that "bidirectional plasticity" impairment may be the electrophysiological hallmark of LID. 42,43 Bidirectional plasticity reflects the property to undergo synaptic neurotransmission depression or potentiation with the same plasticity-inducing protocol, depending on the different receptor state.…”

Section: Pathophysiological Mechanisms Of Lid Dopaminergic Mechanismsmentioning

confidence: 99%

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

Fabbrini¹,

Guerra²

2021

JEP

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L-dopa-induced dyskinesia (LID) is the most frequent motor complication associated with chronic L-dopa treatment in Parkinson’s disease (PD). Recent advances in the understanding of the pathophysiological mechanisms underlying LID suggest that abnormalities in multiple neurotransmitter systems, in addition to dopaminergic nigrostriatal denervation and altered dopamine release and reuptake dynamics at the synaptic level, are involved in LID development. Increased knowledge of neurobiological LID substrates has led to the development of several drug candidates to alleviate this motor complication. However, with the exception of amantadine, none of the pharmacological therapies tested in humans have demonstrated clinically relevant beneficial effects. Therefore, LID management is still one of the most challenging problems in the treatment of PD patients. In this review, we first describe the known pathophysiological mechanisms of LID. We then provide an updated report of experimental pharmacotherapies tested in clinical trials of PD patients and drugs currently under study to alleviate LID. Finally, we discuss available pharmacological LID treatment approaches and offer our opinion of possible issues to be clarified and future therapeutic strategies.

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Section: Pathophysiological Mechanisms Of Lid Dopaminergic Mechanismsmentioning

confidence: 99%

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

Fabbrini¹,

Guerra²

2021

JEP

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“…Furthermore, the dopaminergic receptor DRD1 was found to be differentially rhythmic in NR1D1 KO cells, and showed a phase delay compared to WT cells. Aberrant interactions between different dopamine receptors in the brain may be involved in L-dopa-induced dyskinesia [ 140 ] and risk of hallucination [ 141 ], and based on our findings circadian factors might also be involved in this interplay. Moreover, a regulator of vesicle trafficking, LRRK2 , which is a frequently mutated gene in PD [ 142 , 143 ], has been shown to impair DRD1 signalling transduction in mice [ 144 ].…”

Section: Discussionmentioning

confidence: 67%

A Computational Analysis in a Cohort of Parkinson’s Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes

Yalçin

Malhan

Basti

et al. 2021

Cancers

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Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in DBP, GBA, TEF, SNCA, SERPINA1 and TGFB1. Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., HRAS and GBA) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., TUBB6, PAK6, SLC11A1).

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“…These apparent discrepancies are interesting as they support and confirm that D2R signaling in the striatum affects a majority of cell types and that it is this complexity that has prevented a full knowledge of the D2R implication in LID more than lack of D2R ligands capable of completely distinguish between D2R and D3R ( Lanza et al., 2021 ; Solís et al., 2017 ).…”

Section: Discussionmentioning

confidence: 97%

D2R signaling in striatal spiny neurons modulates L-DOPA induced dyskinesia

Florio¹,

Serra²,

Lewis³

et al. 2022

iScience

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Genetic suppression of the dopamine D3 receptor in striatal D1 cells reduces the development of L-DOPA-induced dyskinesia

Cited by 16 publications

References 41 publications

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

Pathophysiological Mechanisms and Experimental Pharmacotherapy for L-Dopa-Induced Dyskinesia

A Computational Analysis in a Cohort of Parkinson’s Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes

D2R signaling in striatal spiny neurons modulates L-DOPA induced dyskinesia

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