Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment?

Yang, Pengfei; Perlmutter, Joel S.; Benzinger, Tammie L.S.; Morris, John C.; Xu, Jinbin

doi:10.1016/j.arr.2019.100994

Cited by 69 publications

(37 citation statements)

References 244 publications

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“…Availability of high affinity and selective ligands for D3R with good physicochemical and pharmacokinetic properties (i.e., “drug-likeness”) is indispensable for the understanding of the molecular biology, receptor interactions, signaling properties and in vivo functions of the D3R. The other big drive behind the quest for selective agonists, partial agonists or antagonists has been and still is the idea, that such compounds were thought to have great therapeutic potential in the treatment of various CNS diseases such as schizophrenia [ 16 , 102 , 103 , 104 , 105 ], drug abuse [ 9 , 106 ], depression [ 107 , 108 ] or PD [ 79 , 109 ].…”

Section: D3r Ligandsmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson’s disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.

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Section: D3r Ligandsmentioning

confidence: 99%

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

et al. 2021

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“…Although most DR agonists used in PD are designed for D2R activation, 21 and D2R is thought to be the main dopamine therapy target 18 . Other receptors such as D1R and D3R may also be involved as DR agonists showed reduced neuroprotective effects throughout treatment but the loss of all protective effects was not seen when D2R was knocked out 22 .…”

Section: Discussionmentioning

confidence: 99%

“…It has long been accepted that decreases in D1R density are directly correlated with PD symptoms 23 and the increased striatal D1R density is a critical indicator for DR agonists’ clinical sensitivity 24 . While D3R is reported to be decreased in drug‐naive PD patients 25 and considered as a potential target for PD intervention 21 . A D1R preferential agonist, dihydrexidine (with D1R:D2R 10 fold selectivity), was reported to attenuate parkinsonian that can be blunted by a D1R antagonist in a rat PD model 26 .…”

Section: Discussionmentioning

confidence: 99%

Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features

Yang

Knight

et al. 2020

Ann Clin Transl Neurol

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ObjectiveDopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) – are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.MethodsWe analyzed the densities of D1R, D2R, and D3R in the striatum and substantia nigra (SN) using a novel quantitative autoradiography procedure previously developed by our group. We also examined the expression of D2R and D3R mRNA in the striatum by in situ hybridization.ResultsThe results showed that although no differences of striatal D1R were found among all groups; D2R was significantly decreased in the striatum of PD patients when compared with control and AD patients. Some clinical manifestations: age of onset, PD stage, dopamine responsiveness, and survival time after onset; showed a better correlation with striatal D1R + D3R densities combined compared to D1R or D3R alone.InterpretationThere is a possibility that we may infer the results in diagnosis, treatment, and prognosis of PD by detecting D1R + D3R as opposed to using dopamine D1 or D3 receptors alone. This is especially true for elderly patients with low D2R expression as is common in this disease.

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“…Moreover, we show that C. elegans DOP-2, a D3-receptor (D3R) homolog, is required for nicotine-mediated protection. D3Rs are selectively expressed in nigrostriatal DNs where they function as auto-receptors (Joyce & Millan, 2007;Yang, Perlmutter, Benzinger, Morris, & Xu, 2020). The involvement of D3Rs in nicotine-mediated protection may further explain the selective protection afforded to DNs by tobacco smoking, as a source of chronic nicotine exposure.…”

Section: Introductionmentioning

confidence: 99%

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

Nourse

Harshefi

Marom

et al. 2020

Preprint

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Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson's disease (PD), whose hallmark is degeneration of substantia nigra dopaminergic neurons (DNs). We use C. elegans as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model we demonstrate conserved functions of DNexpressed nAChRs. We find that DOP-2, a D3-receptor homolog, MCU-1, a mitochondrial calcium uniporter, and PINK-1, PTEN-induced kinase 1, are required for nicotine-mediated protection of DNs. Together, our results support involvement of calcium-dependent mitochondrial stress activation of PINK-1 in nicotine-dependent neuroprotection. This suggests that nicotine's selective protection of substantia nigra DNs is due to the confluence of two factors: first, their unique vulnerability to mitochondrial stress, which is mitigated by increased mitochondrial quality control due to PINK1 activation; and second, to their specific expression of D3 receptors.Epidemiological studies show that tobacco smoking reduces the prevalence of Parkinson's disease (PD) (Li et al., 2015). A hallmark of PD is degeneration of substantia nigra dopaminergic neurons (DNs). Effects of tobacco smoking on degeneration of these neurons may depend on tobacco-derived nicotine and on nicotinic acetylcholine receptors (nAChRs). Support for this hypothesis comes from several lines of evidence. These include: i)

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Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment?

Cited by 69 publications

References 244 publications

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

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