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Dopamine Receptor in Health and Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-inspired Molecules".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 44567

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Dr. Damiana Leo

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Université de Mons, Mons, Belgium
Interests: dopamine; fast scan cyclic voltammetry (FSCV); neurophramacology; dopamine transporter; attention deficit hyperactivity disorder (ADHD); Parkinson’s disease; gluatamate/dopamine interaction; trace amines; trace amines associated receptor 1 (TAAR1)

Special Issue Information

Dear Colleagues,

Dopamine is the major catecholamine in the central nervous system. It is involved in the regulation of a variety of functions, including locomotor activity, emotion and affect, and neuroendocrine secretion. The dopamine system has been the focus of much research during the past 30 years, mainly because alterations in dopamine neurotransmission are involved, directly or indirectly, in several brain dysfunctions. Dysfunction of dopamine neurotransmission and its receptors leads to several pathological conditions, such as hyperprolactinemia, Parkinson’s disease, schizophrenia, Tourette syndrome, attention deficit/hyperactivity disorder, and Huntington disease. Dopamine receptor agonists and antagonists are used to alleviate symptoms associated with these conditions. Several powerful classes of drugs target the dopamine system, including the antipsychotic medications that bind to the dopamine D2 receptor, and the common recreational drugs cocaine and amphetamine. Significant efforts have been made by the scientific community to understand the biology, mode of action, targets, functions, and signaling mechanisms of dopamine and its receptors.

In this Special Issue of Biomolecules called “Dopamine Receptors in Health and Disease”, we would like to include a variety of perspectives from clinical and disease-based research to more basic studies investigating fundamental biological questions. We would like to review the current state of knowledge about dopamine receptor biology and signaling, the role the dopamine system plays in disease, and how new discoveries may form the basis of novel therapeutic approaches.

Dr. Damiana Leo
Guest Editor

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Keywords

Dopamine receptors
Dopamine
Dopaminergic disease
Neurodegeneration
Parkinson’s disease
Schizophrenia

Published Papers (10 papers)

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Research

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13 pages, 1980 KiB

Open AccessArticle

Pharmacological and Genetic Evidence of Dopamine Receptor 3-Mediated Vasoconstriction in Isolated Mouse Aorta

by Veronica Zingales, Sebastiano Alfio Torrisi, Gian Marco Leggio, Claudio Bucolo, Filippo Drago and Salvatore Salomone

Biomolecules 2021, 11(3), 418; https://doi.org/10.3390/biom11030418 - 11 Mar 2021

Cited by 3 | Viewed by 1791

Abstract

Dopamine receptors (DRs) are generally considered as mediators of vasomotor functions. However, when used in pharmacological studies, dopamine and/or DR agonists may not discriminate among different DR subtypes and may even stimulate alpha1 and beta-adrenoceptors. Here, we tested the hypothesis that D2R and/or D3R may specifically induce vasoconstriction in isolated mouse aorta. Aorta, isolated from wild-type (WT) and D3R⁻/⁻ mice, was mounted in a wire myograph and challenged with cumulative concentrations of phenylephrine (PE), acetylcholine (ACh), and the D3R agonist 7-hydrxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT), with or without the D2R antagonist L741,626 and the D3R antagonist SB-277011-A. The vasoconstriction to PE and the vasodilatation to ACh were not different in WT and D3R⁻/⁻; in contrast, the contractile responses to 7-OH-DPAT were significantly weaker in D3R⁻/⁻, though not abolished. L741,626 did not change the contractile response induced by 7-OH-DPAT in WT or in D3R⁻/⁻, whereas SB-277011-A significantly reduced it in WT but did not in D3R⁻/⁻. D3R mRNA (assessed by qPCR) was about 5-fold more abundant than D2R mRNA in aorta from WT and undetectable in aorta from D3R⁻/⁻. Following transduction with lentivirus (72-h incubation) delivering synthetic microRNAs to specifically inactivate D2R (LV-miR-D2) or D3R (LV-miR-D3), the contractile response to 7-OH-DPAT was unaffected by LV-miR-D2, while it was significantly reduced by LV-miR-D3. These data indicate that, at least in mouse aorta, D3R stimulation induces vasoconstriction, while D2R stimulation does not. This is consistent with the higher expression level of D3R. The residual vasoconstriction elicited by high concentration D3R agonist in D3R⁻/⁻ and/or in the presence of D3R antagonist is likely to be unrelated to DRs. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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10 pages, 429 KiB

Open AccessArticle

The Effect of Escitalopram on Central Serotonergic and Dopaminergic Systems in Patients with Cervical Dystonia, and Its Relationship with Clinical Treatment Effects: A Double-Blind Placebo-Controlled Trial

by Evelien Zoons, Marina A.J. Tijssen, Yasmine E.M. Dreissen, Marenka Smit and Jan Booij

Biomolecules 2020, 10(6), 880; https://doi.org/10.3390/biom10060880 - 08 Jun 2020

Cited by 8 | Viewed by 3381

Abstract

Purpose: The pathophysiology of cervical dystonia (CD) is thought to be related to changes in dopamine and serotonin levels in the brain. We performed a double-blind trial with escitalopram (selective serotonin reuptake inhibitor; SSRI) in patients with CD. Here, we report on changes in dopamine D_2/3 receptor (D2/3R), dopamine transporter (DAT) and serotonin transporter (SERT) binding potential (BP_ND) after a six-week treatment course with escitalopram or placebo. Methods: CD patients had [123I]FP-CIT SPECT (I-123 fluoropropyl carbomethoxy-3 beta-(4-iodophenyltropane) single-photon emission computed tomography) scans, to quantify extrastriatal SERT and striatal DAT, and [123I]IBZM SPECT (I-123 iodobenzamide SPECT) scans to quantify striatal D2/3R BPND before and after six weeks of treatment with either escitalopram or placebo. Treatment effect was evaluated with the Clinical Global Impression scale for dystonia, jerks and psychiatric symptoms, both by physicians and patients. Results: In both patients treated with escitalopram and placebo there were no significant differences after treatment in SERT, DAT or D2/3R BP_ND. Comparing scans after treatment with escitalopram (n = 8) to placebo (n = 8) showed a trend (p = 0.13) towards lower extrastriatal SERT BPND in the SSRI group (median SERT occupancy of 64.6%). After treatment with escitalopram, patients who reported a positive effect on dystonia or psychiatric symptoms had significantly higher SERT occupancy compared to patients who did not experience an effect. Conclusion: Higher extrastriatal SERT occupancy after treatment with escitalopram is associated with a trend towards a positive subjective effect on dystonia and psychiatric symptoms in CD patients. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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25 pages, 6956 KiB

Open AccessArticle

Rats Lacking Dopamine Transporter Display Increased Vulnerability and Aberrant Autonomic Response to Acute Stress

by Placido Illiano, Gregory E. Bigford, Raul R. Gainetdinov and Marta Pardo

Biomolecules 2020, 10(6), 842; https://doi.org/10.3390/biom10060842 - 31 May 2020

Cited by 14 | Viewed by 4005

Abstract

The activity of the hypothalamus–pituitary–adrenal (HPA) axis is pivotal in homeostasis and presides the adaptative response to stress. Dopamine Transporter (DAT) plays a key role in the regulation of the HPA axis. We used young adult female DAT Knockout (KO) rats to assess the effects of DAT ablation (partial, heterozygous DAT+/-, or total, homozygous DAT-/-) on vulnerability to stress. DAT-/- rats show profound dysregulation of pituitary homeostasis, in the presence of elevated peripheral corticosterone, before and after acute restraint stress. During stress, DAT-/- rats show abnormal autonomic response at either respiratory and cardiovascular level, and delayed body temperature increase. DAT+/- rats display minor changes of hypophyseal homeostatic mechanisms. These rats display a similar pituitary activation to that of the control animals, albeit in the presence of higher release of peripheral corticosterone than DAT-/- after stress, and reduced temperature during stress. Our data indicate that DAT regulates the HPA axis at both the central and peripheral level, including autonomic function during stress. In particular, the partial deletion of DAT results in increased vulnerability to stress in female rats, which display central and peripheral alterations that are reminiscent of PTSD, and they might provide new insights in the pathophysiology of this disorder. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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22 pages, 2737 KiB

Open AccessArticle

Blockade of Intranigral and Systemic D3 Receptors Stimulates Motor Activity in the Rat Promoting a Reciprocal Interaction among Glutamate, Dopamine, and GABA

by Marina Rodríguez-Sánchez, Rodrigo Erick Escartín-Pérez, Gerardo Leyva-Gómez, José Arturo Avalos-Fuentes, Francisco Javier Paz-Bermúdez, Santiago Iván Loya-López, Jorge Aceves, David Erlij, Hernán Cortés and Benjamín Florán

Biomolecules 2019, 9(10), 511; https://doi.org/10.3390/biom9100511 - 20 Sep 2019

Cited by 6 | Viewed by 3674

Abstract

In vivo activation of dopamine D3 receptors (D3Rs) depresses motor activity. D3Rs are widely expressed in subthalamic, striatal, and dendritic dopaminergic inputs into the substantia nigra pars reticulata (SNr). In vitro studies showed that nigral D3Rs modulate their neurotransmitter release; thus, it could be that these changes in neurotransmitter levels modify the discharge of nigro-thalamic neurons and, therefore, motor behavior. To determine how the in vitro responses correspond to the in vivo responses, we examined the effect of intra-nigral and systemic blockade of D3Rs in the interstitial content of glutamate, dopamine, and GABA within the SNr using microdialysis coupled to motor activity determinations in freely moving rats. Intranigral unilateral blockade of D3R with GR 103,691 increased glutamate, dopamine, and GABA. Increments correlated with increased ambulatory distance, non-ambulatory activity, and induced contralateral turning. Concomitant blockade of D3R with D1R by perfusion of SCH 23390 reduced the increase of glutamate; prevented the increment of GABA, but not of dopamine; and abolished behavioral effects. Glutamate stimulates dopamine release by NMDA receptors, while blockade with kynurenic acid prevented the increase in dopamine and, in turn, of GABA and glutamate. Finally, systemic administration of D3R selective antagonist U 99194A increased glutamate, dopamine, and GABA in SNr and stimulated motor activity. Blockade of intra-nigral D1R with SCH 23390 prior to systemic U 99194A diminished increases in neurotransmitter levels and locomotor activity. These data highlight the pivotal role of presynaptic nigral D3 and D1R in the control of motor activity and help to explain part of the effects of the in vivo administration of D3R agents. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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19 pages, 1655 KiB

Open AccessArticle

Severity of Dyskinesia and D3R Signaling Changes Induced by L-DOPA Treatment of Hemiparkinsonian Rats Are Features Inherent to the Treated Subjects

by Sacnité Albarrán-Bravo, José Arturo Ávalos-Fuentes, Hernán Cortés, Marina Rodriguez-Sánchez, Norberto Leyva-García, Claudia Rangel-Barajas, David Erlij and Benjamín Florán

Biomolecules 2019, 9(9), 431; https://doi.org/10.3390/biom9090431 - 01 Sep 2019

Cited by 6 | Viewed by 2749

Abstract

Extensive damage to nigrostriatal dopaminergic neurons leads to Parkinson’s disease (PD). To date, the most effective treatment has been administration of levodopa (L-DOPA) to increase dopaminergic tone. This treatment leads to responses that vary widely among patients, from predominantly beneficial effects to the induction of disabling, abnormal movements (L-DOPA induced dyskinesia (LID)). Similarly, experimental studies have shown animals with widely different degrees of LID severity. In this study, unilateral injections of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB) produced more than 90% depletion of dopamine in both the striatum and the substantia nigra reticulata (SNr) of rats. Population analysis showed that dopamine depletion levels were clustered in a single population. In contrast, analysis of abnormal involuntary movements (AIMs) induced by L-DOPA treatment of 6-OHDA-lesioned animals yielded two populations: one with mild LID, and the other with severe LID, which are also related to different therapeutic responses. We examined whether the severity of LID correlated with changes in dopamine 3 receptor (D3R) signaling because of the following: (a) D3R expression and the induction of LID are strongly correlated; and (b) dopaminergic denervation induces a qualitative change in D3R signaling in the SNr. We found that the effects of D3R activation on cAMP accumulation and depolarization-induced [³H]-gamma-aminobutyric acid ([³H]-GABA) release were switched. L-DOPA treatment normalized the denervation-induced changes in animals with mild LID. The D3R activation caused depression of both dopamine 1 receptor (D1R)-induced increases in cAMP production and depolarization-induced [³H]-GABA release, which were reversed to their pre-denervation state. In animals with severe LID, none of the denervation-induced changes were reversed. The finding that in the absence of identifiable differences in 6-OHDA and L-DOPA treatment, two populations of animals with different D3R signaling and LIDs severity implies that mechanisms intrinsic to the treated subject determine the segregation. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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17 pages, 2550 KiB

Open AccessArticle

Heterodimerization of Mu Opioid Receptor Protomer with Dopamine D₂ Receptor Modulates Agonist-Induced Internalization of Mu Opioid Receptor

by Lakshmi Vasudevan, Dasiel O. Borroto-Escuela, Jelle Huysentruyt, Kjell Fuxe, Deepak K. Saini and Christophe Stove

Biomolecules 2019, 9(8), 368; https://doi.org/10.3390/biom9080368 - 14 Aug 2019

Cited by 10 | Viewed by 5251

Abstract

The interplay between the dopamine (DA) and opioid systems in the brain is known to modulate the additive effects of substances of abuse. On one hand, opioids serve mankind by their analgesic properties, which are mediated via the mu opioid receptor (MOR), a Class A G protein-coupled receptor (GPCR), but on the other hand, they pose a potential threat by causing undesired side effects such as tolerance and dependence, for which the exact molecular mechanism is still unknown. Using human embryonic kidney 293T (HEK 293T) and HeLa cells transfected with MOR and the dopamine D₂ receptor (D₂R), we demonstrate that these receptors heterodimerize, using an array of biochemical and biophysical techniques such as coimmunoprecipitation (co-IP), bioluminescence resonance energy transfer (BRET¹), Fӧrster resonance energy transfer (FRET), and functional complementation of a split luciferase. Furthermore, live cell imaging revealed that D_2LR, when coexpressed with MOR, slowed down internalization of MOR, following activation with the MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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Review

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16 pages, 1135 KiB

Open AccessReview

Dopamine Receptors and the Kidney: An Overview of Health- and Pharmacological-Targeted Implications

by Alejandro Olivares-Hernández, Luis Figuero-Pérez, Juan Jesus Cruz-Hernandez, Rogelio González Sarmiento, Ricardo Usategui-Martin and José Pablo Miramontes-González

Biomolecules 2021, 11(2), 254; https://doi.org/10.3390/biom11020254 - 10 Feb 2021

Cited by 28 | Viewed by 6221

Abstract

The dopaminergic system can adapt to the different physiological or pathological situations to which the kidneys are subjected throughout life, maintaining homeostasis of natriuresis, extracellular volume, and blood pressure levels. The role of renal dopamine receptor dysfunction is clearly established in the pathogenesis of essential hypertension. Its associations with other pathological states such as insulin resistance and redox balance have also been associated with dysfunction of the dopaminergic system. The different dopamine receptors (D1–D5) show a protective effect against hypertension and kidney disorders. It is essential to take into account the various interactions of the dopaminergic system with other elements, such as adrenergic receptors. The approach to therapeutic strategies for essential hypertension must go through the blocking of those elements that lead to renal vasoconstriction or the restoration of the normal functioning of dopamine receptors. D1-like receptors are fundamental in this role, and new therapeutic efforts should be directed to the restoration of their functioning in many patients. More studies will be needed to allow the development of drugs that can be targeted to renal dopamine receptors in the treatment of hypertension. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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18 pages, 643 KiB

Open AccessReview

Critical Impact of Different Conserved Endoplasmic Retention Motifs and Dopamine Receptor Interacting Proteins (DRIPs) on Intracellular Localization and Trafficking of the D₂ Dopamine Receptor (D₂-R) Isoforms

by Kaja Blagotinšek Cokan, Maša Mavri, Catrin Sian Rutland, Sanja Glišić, Milan Senćanski, Milka Vrecl and Valentina Kubale

Biomolecules 2020, 10(10), 1355; https://doi.org/10.3390/biom10101355 - 23 Sep 2020

Cited by 9 | Viewed by 4232

Abstract

The type 2 dopamine receptor D₂ (D₂-R), member of the G protein-coupled receptor (GPCR) superfamily, exists in two isoforms, short (D_2S-R) and long (D_2L-R). They differ by an additional 29 amino acids (AA) in the third cytoplasmic loop (ICL3) of the D_2L-R. These isoforms differ in their intracellular localization and trafficking functionality, as D_2L-R possesses a larger intracellular pool, mostly in the endoplasmic reticulum (ER). This review focuses on the evolutionarily conserved motifs in the ICL3 of the D₂-R and proteins interacting with the ICL3 of both isoforms, specifically with the 29 AA insert. These motifs might be involved in D₂-R exit from the ER and have an impact on cell-surface and intracellular localization and, therefore, also play a role in the function of dopamine receptor signaling, ligand binding and possible homo/heterodimerization. Our recent bioinformatic data on potential new interaction partners for the ICL3 of D₂-Rs are also presented. Both are highly relevant, and have clinical impacts on the pathophysiology of several diseases such as Parkinson’s disease, schizophrenia, Tourette’s syndrome, Huntington’s disease, manic depression, and others, as they are connected to a variety of essential motifs and differences in communication with interaction partners. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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21 pages, 2450 KiB

Open AccessFeature PaperReview

Noncoding RNAs and Midbrain DA Neurons: Novel Molecular Mechanisms and Therapeutic Targets in Health and Disease

by Emilia Pascale, Giuseppina Divisato, Renata Palladino, Margherita Auriemma, Edward Faustine Ngalya and Massimiliano Caiazzo

Biomolecules 2020, 10(9), 1269; https://doi.org/10.3390/biom10091269 - 03 Sep 2020

Cited by 11 | Viewed by 4898

Abstract

Midbrain dopamine neurons have crucial functions in motor and emotional control and their degeneration leads to several neurological dysfunctions such as Parkinson’s disease, addiction, depression, schizophrenia, and others. Despite advances in the understanding of specific altered proteins and coding genes, little is known about cumulative changes in the transcriptional landscape of noncoding genes in midbrain dopamine neurons. Noncoding RNAs—specifically microRNAs and long noncoding RNAs—are emerging as crucial post-transcriptional regulators of gene expression in the brain. The identification of noncoding RNA networks underlying all stages of dopamine neuron development and plasticity is an essential step to deeply understand their physiological role and also their involvement in the etiology of dopaminergic diseases. Here, we provide an update about noncoding RNAs involved in dopaminergic development and metabolism, and the related evidence of these biomolecules for applications in potential treatments for dopaminergic neurodegeneration. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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15 pages, 503 KiB

Open AccessEditor’s ChoiceReview

Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

by Federica Bono, Veronica Mutti, Chiara Fiorentini and Cristina Missale

Biomolecules 2020, 10(7), 1016; https://doi.org/10.3390/biom10071016 - 09 Jul 2020

Cited by 26 | Viewed by 6927

Abstract

The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson’s disease (PD), and a target for drug design. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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