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Biomedicines
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Dopamine Signaling Pathway in Health and Disease
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Dopamine Signaling Pathway in Health and Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 26840

Special Issue Editors

Prof. Dr. Floriana Volpicelli

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Guest Editor
Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131, Naples, Italy
Interests: synaptic plasticity; synaptic transmission; signaling pathways; regulation of gene expression
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria Concetta Miniaci

E-Mail Website
Guest Editor
Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, 80131, Naples, Italy
Interests: Neuromodulation; synaptic plasticity; learning and memory; neurodegeneration
Special Issues, Collections and Topics in MDPI journals
Dr. Luisa Speranza

E-Mail Website
Guest Editor
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA
Interests: neuronal plasticity and homeostasis; autophagy; protein synthesis; intellectual disability
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Dopamine is a key neurotransmitter modulating multiple and essential physiological functions of the central nervous system, including motor behavior, affective and emotional states, reward and reinforcement behaviors, and other higher cognitive functions. The four major dopaminergic pathways are the nigrostriatal, the mesocortical, the mesolimbic, and the tuberoinfundibular pathway.

Dysfunction in the dopaminergic transmission is recognized as a core alteration in several neurological and psychiatric disorders, including Parkinson’s disease, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD), and addiction.

This Special Issue on the “Dopamine Signaling Pathway in Health and Disease” will present a selection of original research papers and reviews concerning the cellular and molecular mechanisms underlying dopaminergic neuromodulation under physiological conditions and in preclinical cellular and animal models of dopaminergic neurodegeneration as well as novel potential pharmacological approaches for dopamine-related disorders.

Prof. Dr. Floriana Volpicelli
Prof. Dr. Maria Concetta Miniaci
Dr. Luisa Speranza
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • differentiation
  • disease modeling
  • dopamine and drugs
  • gene expression
  • human stem cells
  • neuronal development
  • reprogramming
  • signaling pathways
  • neurodegeneration
  • neuromodulation

Published Papers (13 papers)

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Research

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18 pages, 3144 KiB  
Article
Modulation of D3R Splicing, Signaling, and Expression by D1R through PKA→PTB Phosphorylation
by Orlando Casados-Delgado, José Arturo Avalos-Fuentes, Manuel Lara-Lozano, Gisela Tovar-Medina, Carla Daniela Florán-Hernández, Karla Gisela Martínez-Nolasco, Hernán Cortes, Ricardo Felix, José Segovia and Benjamín Florán
Biomedicines 2024, 12(1), 206; https://doi.org/10.3390/biomedicines12010206 - 17 Jan 2024
Viewed by 822
Abstract
The D1R and D3R receptors functionally and synergistically interact in striatonigral neurons. Dopaminergic denervation turns this interaction antagonistic, which is correlated with a decrement in D3nf isoform and an increment in D3R membranal expression. The [...] Read more.
The D1R and D3R receptors functionally and synergistically interact in striatonigral neurons. Dopaminergic denervation turns this interaction antagonistic, which is correlated with a decrement in D3nf isoform and an increment in D3R membranal expression. The mechanisms of such changes in D3R are attributed to the dysregulation of the expression of their isoforms. The cause and mechanism of this phenomenon remain unknown. Dopaminergic denervation produces a decrement in D1R and PKA activity; we propose that the lack of phosphorylation of PTB (regulator of alternative splicing) by PKA produces the dysregulation of D3R splicing and changes D3R functionality. By using in silico analysis, we found that D3R mRNA has motifs for PTB binding and, by RIP, co-precipitates with PTB. Moreover, D1R activation via PKA promotes PTB phosphorylation. Acute and 5-day D1R blockade decreases the expression of D3nf mRNA. The 5-day treatment reduces D3R, D3nf, and PTB protein in the cytoplasm and increases D3R in the membrane and PTB in the nucleus. Finally, the blockade of D1R mimics the effect of dopaminergic denervation in D1R and D3R signaling. Thus, our data indicate that through PKA→PTB, D1R modulates D3R splicing, expression, and signaling, which are altered during D1R blockade or the lack of stimulation in dopaminergic denervation. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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13 pages, 1377 KiB  
Article
2,4-Dichlorophenoxyacetic Acid Induces Degeneration of mDA Neurons In Vitro
by Tamara Russ, Lennart Enders, Julia M. Zbiegly, Phani Sankar Potru, Johannes Wurm and Björn Spittau
Biomedicines 2023, 11(11), 2882; https://doi.org/10.3390/biomedicines11112882 - 24 Oct 2023
Viewed by 2024
Abstract
Background: Parkinson’s disease (PD) affects 1–2% of the population over the age of 60 and the majority of PD cases are sporadic, without any family history of the disease. Neuroinflammation driven by microglia has been shown to promote the progression of midbrain dopaminergic [...] Read more.
Background: Parkinson’s disease (PD) affects 1–2% of the population over the age of 60 and the majority of PD cases are sporadic, without any family history of the disease. Neuroinflammation driven by microglia has been shown to promote the progression of midbrain dopaminergic (mDA) neuron loss through the release of neurotoxic factors. Interestingly, the risk of developing PD is significantly higher in distinct occupations, such as farming and agriculture, and is linked to the use of pesticides and herbicides. Methods: The neurotoxic features of 2,4-Dichlorophenoxyacetic acid (2,4D) at concentrations of 10 µM and 1 mM were analyzed in two distinct E14 midbrain neuron culture systems and in primary microglia. Results: The application of 1 mM 2,4D resulted in mDA neuron loss in neuron-enriched cultures. Notably, 2,4D-induced neurotoxicity significantly increased in the presence of microglia in neuron-glia cultures, suggesting that microglia-mediated neurotoxicity could be one mechanism for progressive neuron loss in this in vitro setup. However, 2,4D alone was unable to trigger microglia reactivity. Conclusions: Taken together, we demonstrate that 2,4D is neurotoxic for mDA neurons and that the presence of glia cells enhances 2,4D-induced neuron death. These data support the role of 2,4D as a risk factor for the development and progression of PD and further suggest the involvement of microglia during 2,4D-induced mDA neuron loss. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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13 pages, 579 KiB  
Article
Alterations in Serotonin Neurotransmission in Hyperdopaminergic Rats Lacking the Dopamine Transporter
by Dmitrii S. Traktirov, Ilya R. Nazarov, Valeria S. Artemova, Raul R. Gainetdinov, Nina S. Pestereva and Marina N. Karpenko
Biomedicines 2023, 11(11), 2881; https://doi.org/10.3390/biomedicines11112881 - 24 Oct 2023
Viewed by 1099
Abstract
Biogenic amines dopamine (DA) and serotonin (5-HT) are among the most significant monoaminergic neurotransmitters in the central nervous system (CNS). Separately, the physiological roles of DA and 5-HT have been studied in detail, and progress has been made in understanding their roles in [...] Read more.
Biogenic amines dopamine (DA) and serotonin (5-HT) are among the most significant monoaminergic neurotransmitters in the central nervous system (CNS). Separately, the physiological roles of DA and 5-HT have been studied in detail, and progress has been made in understanding their roles in normal and various pathological conditions (Parkinson’s disease, schizophrenia, addiction, depression, etc.). In this article we showed that knockout of the gene encoding DAT leads not only to a profound dysregulation of dopamine neurotransmission in the striatum but also in the midbrain, prefrontal cortex, hippocampus, medulla oblongata and spinal cord. Furthermore, significant changes were observed in the production of mRNA of enzymes of monoamine metabolism, as well as to a notable alteration in the tissue level of serotonin, most clearly manifested in the cerebellum and the spinal cord. The observed region-specific changes in the tissue levels of serotonin and in the expression of dopamine and serotonergic metabolism enzymes in rats with an excess of dopamine can indicate important consequences for the pharmacotherapy of drugs that modulate the dopaminergic system. The drugs that affect the dopaminergic system could potently affect the serotonergic system, and this fact is important to consider when predicting their possible therapeutic or side effects. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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22 pages, 1697 KiB  
Article
Characterization of Behavioral Phenotypes in Heterozygous DAT Rat Based on Pedigree
by Gioia Zanfino, Concetto Puzzo, Vincenzo de Laurenzi and Walter Adriani
Biomedicines 2023, 11(9), 2565; https://doi.org/10.3390/biomedicines11092565 - 18 Sep 2023
Cited by 1 | Viewed by 965
Abstract
Dopamine is an essential neurotransmitter whose key roles include movement control, pleasure and reward, attentional and cognitive skills, and regulation of the sleep/wake cycle. Reuptake is carried out by the dopamine transporter (DAT; DAT1 SLC6A3 gene). In order to study the effects of [...] Read more.
Dopamine is an essential neurotransmitter whose key roles include movement control, pleasure and reward, attentional and cognitive skills, and regulation of the sleep/wake cycle. Reuptake is carried out by the dopamine transporter (DAT; DAT1 SLC6A3 gene). In order to study the effects of hyper-dopaminergia syndrome, the gene was silenced in rats. DAT-KO rats show stereotypical behavior, hyperactivity, a deficit in working memory, and an altered circadian cycle. In addition to KO rats, heterozygous (DAT-HET) rats show relative hypofunction of DAT; exact phenotypic effects are still unknown and may depend on whether the sire or the dam was KO. Our goal was to elucidate the potential importance of the parental origin of the healthy or silenced allele and its impact across generations, along with the potential variations in maternal care. We thus generated specular lines to study the effects of (grand) parental roles in inheriting the wild or mutated allele. MAT-HETs are the progeny of a KO sire and a WT dam; by breeding MAT-HET males and KO females, we obtained subjects with a DAT -/- epigenotype, named QULL, to reflect additional epigenetic DAT modulation when embryos develop within a hyper-dopaminergic KO uterus. We aimed to verify if any behavioral anomaly was introduced by a QULL (instead of KO) rat acting as a direct father or indirect maternal grandfather (or both). We thus followed epigenotypes obtained after three generations and observed actual effects on impaired maternal care of the offspring (based on pedigree). In particular, offspring of MAT-HET-dam × QULL-sire breeding showed a compulsive and obsessive phenotype. Although the experimental groups were all heterozygous, the impact of having a sire of epigenotype QULL (who developed in the uterus of a KO grand-dam) has emerged clearly. Along the generations, the effects of the DAT epigenotype on the obsessive/compulsive phenotype do vary as a function of the uterine impact on either allele in one’s genealogical line. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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23 pages, 3135 KiB  
Article
Gender-Specific Interactions in a Visual Object Recognition Task in Persons with Opioid Use Disorder
by JoAnn Petrie, Logan R. Kowallis, Sarah Kamhout, Kyle B. Bills, Daniel Adams, Donovan E. Fleming, Bruce L. Brown and Scott C. Steffensen
Biomedicines 2023, 11(9), 2460; https://doi.org/10.3390/biomedicines11092460 - 5 Sep 2023
Viewed by 957
Abstract
Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide over the past two decades, with death rates for men reported at twice the rate for women. Using a controlled, cross-sectional, age-matched (18–56 y) design to better understand the cognitive neuroscience of [...] Read more.
Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide over the past two decades, with death rates for men reported at twice the rate for women. Using a controlled, cross-sectional, age-matched (18–56 y) design to better understand the cognitive neuroscience of OUD, we evaluated the electroencephalographic (EEG) responses of male and female participants with OUD vs. age- and gender-matched non-OUD controls during a simple visual object recognition Go/No-Go task. Overall, women had significantly slower reaction times (RTs) than men. In addition, EEG N200 and P300 event-related potential (ERP) amplitudes for non-OUD controls were significantly larger for men, while their latencies were significantly shorter than for women. However, while N200 and P300 amplitudes were not significantly affected by OUD for either men or women in this task, latencies were also affected differentially in men vs. women with OUD. Accordingly, for both N200 and P300, male OUD participants exhibited longer latencies while female OUD participants exhibited shorter ones than in non-OUD controls. Additionally, robust oscillations were found in all participants during a feedback message associated with performance in the task. Although alpha and beta power during the feedback message were significantly greater for men than women overall, both alpha and beta oscillations exhibited significantly lower power in all participants with OUD. Taken together, these findings suggest important gender by OUD differences in cognitive processing and reflection of performance in this simple visual task. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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21 pages, 2041 KiB  
Article
Interaction of Brain-Derived Neurotrophic Factor with the Effects of Chronic Methamphetamine on Prepulse Inhibition in Mice Is Independent of Dopamine D3 Receptors
by Samuel Hogarth, Emily J. Jaehne, Xiangjun Xu, Quenten Schwarz and Maarten van den Buuse
Biomedicines 2023, 11(8), 2290; https://doi.org/10.3390/biomedicines11082290 - 17 Aug 2023
Viewed by 1020
Abstract
The aim of the present study was to gain a better understanding of the role of brain-derived neurotrophic factor (BDNF) and dopamine D3 receptors in the effects of chronic methamphetamine (METH) on prepulse inhibition (PPI), an endophenotype of psychosis. We compared the effect [...] Read more.
The aim of the present study was to gain a better understanding of the role of brain-derived neurotrophic factor (BDNF) and dopamine D3 receptors in the effects of chronic methamphetamine (METH) on prepulse inhibition (PPI), an endophenotype of psychosis. We compared the effect of a three-week adolescent METH treatment protocol on the regulation of PPI in wildtype mice, BDNF heterozygous mice (HET), D3 receptor knockout mice (D3KO), and double-mutant mice (DM) with both BDNF heterozygosity and D3 receptor knockout. Chronic METH induced disruption of PPI regulation in male mice with BDNF haploinsufficiency (HET and DM), independent of D3 receptor knockout. Specifically, these mice showed reduced baseline PPI, as well as attenuated disruption of PPI induced by acute treatment with the dopamine receptor agonist, apomorphine (APO), or the glutamate NMDA receptor antagonist, MK-801. In contrast, there were no effects of BDNF heterozygosity or D3 knockout on PPI regulation in female mice. Chronic METH pretreatment induced the expected locomotor hyperactivity sensitisation, where female HET and DM mice also showed endogenous sensitisation. Differential sex-specific effects of genotype and METH pretreatment were observed on dopamine receptor and dopamine transporter gene expression in the striatum and frontal cortex. Taken together, these results show a significant involvement of BDNF in the long-term effects of METH on PPI, particularly in male mice, but these effects appear independent of D3 receptors. The role of this receptor in psychosis endophenotypes therefore remains unclear. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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24 pages, 4094 KiB  
Article
Dopamine Receptor Ligand Selectivity—An In Silico/In Vitro Insight
by Lukas Zell, Alina Bretl, Veronika Temml and Daniela Schuster
Biomedicines 2023, 11(5), 1468; https://doi.org/10.3390/biomedicines11051468 - 17 May 2023
Viewed by 1672
Abstract
Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for one [...] Read more.
Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson’s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the U.S. Food and Drug Administration (FDA), only a very small number are truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico/in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D2R/D3R-selective ligands (micro- to nanomolar binding affinities, D3R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D3R activity (Ki = 2.3 nM) with 263.7-fold D2R/D3R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting the selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of the structural motifs responsible for DR subtype selectivity, thus benefitting drug development in D2R/D3R-associated pathologies such as PD. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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Review

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16 pages, 2690 KiB  
Review
Prefrontal Dopamine in Flexible Adaptation to Environmental Changes: A Game for Two Players
by Emanuele Claudio Latagliata, Cristina Orsini, Simona Cabib, Francesca Biagioni, Francesco Fornai and Stefano Puglisi-Allegra
Biomedicines 2023, 11(12), 3189; https://doi.org/10.3390/biomedicines11123189 - 30 Nov 2023
Viewed by 880
Abstract
Deficits in cognitive flexibility have been characterized in affective, anxiety, and neurodegenerative disorders. This paper reviews data, mainly from studies on animal models, that support the existence of a cortical–striatal brain circuit modulated by dopamine (DA), playing a major role in cognitive/behavioral flexibility. [...] Read more.
Deficits in cognitive flexibility have been characterized in affective, anxiety, and neurodegenerative disorders. This paper reviews data, mainly from studies on animal models, that support the existence of a cortical–striatal brain circuit modulated by dopamine (DA), playing a major role in cognitive/behavioral flexibility. Moreover, we reviewed clinical findings supporting misfunctioning of this circuit in Parkinson’s disease that could be responsible for some important non-motoric symptoms. The reviewed findings point to a role of catecholaminergic transmission in the medial prefrontal cortex (mpFC) in modulating DA’s availability in the nucleus accumbens (NAc), as well as a role of NAc DA in modulating the motivational value of natural and conditioned stimuli. The review section is accompanied by a preliminary experiment aimed at testing weather the extinction of a simple Pavlovian association fosters increased DA transmission in the mpFC and inhibition of DA transmission in the NAc. Full article
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34 pages, 827 KiB  
Review
Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes
by Giuseppe Lisco, Anna De Tullio, Michele Iovino, Olga Disoteo, Edoardo Guastamacchia, Vito Angelo Giagulli and Vincenzo Triggiani
Biomedicines 2023, 11(11), 2993; https://doi.org/10.3390/biomedicines11112993 - 7 Nov 2023
Cited by 2 | Viewed by 5588
Abstract
Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated [...] Read more.
Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated with it. This review summarizes recent evidence on the role of dopamine in regulating insular metabolism and activity, the pathophysiology of traditional chronic complications associated with T2D, the pathophysiological interconnection between T2D and chronic neurological and psychiatric disorders characterized by impaired dopamine activity/metabolism, and therapeutic implications. Reinforcing dopamine signaling is therapeutic in T2D, especially in patients with dopamine-related disorders, such as Parkinson’s and Huntington’s diseases, addictions, and attention-deficit/hyperactivity disorder. On the other hand, although specific trials are probably needed, certain medications approved for T2D (e.g., metformin, pioglitazone, incretin-based therapy, and gliflozins) may have a therapeutic role in such dopamine-related disorders due to anti-inflammatory and anti-oxidative effects, improvement in insulin signaling, neuroinflammation, mitochondrial dysfunction, autophagy, and apoptosis, restoration of striatal dopamine synthesis, and modulation of dopamine signaling associated with reward and hedonic eating. Last, targeting dopamine metabolism could have the potential for diagnostic and therapeutic purposes in chronic diabetes-related complications, such as diabetic retinopathy. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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16 pages, 808 KiB  
Review
From Reward to Anhedonia-Dopamine Function in the Global Mental Health Context
by Birgitta Dresp-Langley
Biomedicines 2023, 11(9), 2469; https://doi.org/10.3390/biomedicines11092469 - 6 Sep 2023
Viewed by 4034
Abstract
When “hijacked” by compulsive behaviors that affect the reward and stress centers of the brain, functional changes in the dopamine circuitry occur as the consequence of pathological brain adaptation. As a brain correlate of mental health, dopamine has a central functional role in [...] Read more.
When “hijacked” by compulsive behaviors that affect the reward and stress centers of the brain, functional changes in the dopamine circuitry occur as the consequence of pathological brain adaptation. As a brain correlate of mental health, dopamine has a central functional role in behavioral regulation from healthy reward-seeking to pathological adaptation to stress in response to adversity. This narrative review offers a spotlight view of the transition from healthy reward function, under the control of dopamine, to the progressive deregulation of this function in interactions with other brain centers and circuits, producing what may be called an anti-reward brain state. How such deregulation is linked to specific health-relevant behaviors is then explained and linked to pandemic-related adversities and the stresses they engendered. The long lockdown periods where people in social isolation had to rely on drink, food, and digital rewards via the internet may be seen as the major triggers of changes in motivation and reward-seeking behavior worldwide. The pathological adaptation of dopamine-mediated reward circuitry in the brain is discussed. It is argued that, when pushed by fate and circumstance into a physiological brain state of anti-reward, human behavior changes and mental health is affected, depending on individual vulnerabilities. A unified conceptual account that places dopamine function at the centre of the current global mental health context is proposed. Full article
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15 pages, 1036 KiB  
Review
The Role of Dopamine in Repurposing Drugs for Oncology
by Catarina Moura and Nuno Vale
Biomedicines 2023, 11(7), 1917; https://doi.org/10.3390/biomedicines11071917 - 6 Jul 2023
Cited by 3 | Viewed by 2599
Abstract
Dopamine is a neurotransmitter that plays an important role within the brain by regulating a wide variety of cognitive and emotional processes. In cancer, its role is distinct and uncertain, but it is characterized by the interaction with its receptors that may be [...] Read more.
Dopamine is a neurotransmitter that plays an important role within the brain by regulating a wide variety of cognitive and emotional processes. In cancer, its role is distinct and uncertain, but it is characterized by the interaction with its receptors that may be in the tumor cells; we have examples of different types of cancer with this characteristic, of which breast and colon cancer stand out. It is believed that dopamine and some of its receptors also influence other cellular processes such as cell proliferation, survival, migration, and invasion. The potential of these receptors has allowed the exploration of existing drugs, originally developed for non-oncological purposes, for the possible treatment of cancer. However, regarding the repurposing of drugs for cancer treatment, the role of dopamine is not so straightforward and needs to be clarified. For this reason, this review intends to present concepts associated with twelve drugs reused for oncology based on dopamine and its receptors. Some of them can behave as antagonists and inhibit tumor cell growth leading to cell death. Attention to this group of drugs may enhance the study of other pharmacological conditions such as signaling pathways related to cell proliferation and migration. Modulation of these pathways using drugs originally developed for other conditions may offer potential therapeutic opportunities in oncology. It is important to note that while the repurposing of oncology drugs based on dopamine signaling is promising, further studies are still needed to fully understand the mechanisms involved and determine the clinical efficacy and safety of these approaches. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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16 pages, 836 KiB  
Review
Na+,K+-ATPase and Cardiotonic Steroids in Models of Dopaminergic System Pathologies
by Alisa A. Markina, Rogneda B. Kazanskaya, Julia A. Timoshina, Vladislav A. Zavialov, Denis A. Abaimov, Anna B. Volnova, Tatiana N. Fedorova, Raul R. Gainetdinov and Alexander V. Lopachev
Biomedicines 2023, 11(7), 1820; https://doi.org/10.3390/biomedicines11071820 - 25 Jun 2023
Cited by 1 | Viewed by 1133
Abstract
In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na+,K+-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the [...] Read more.
In recent years, enough evidence has accumulated to assert that cardiotonic steroids, Na+,K+-ATPase ligands, play an integral role in the physiological and pathophysiological processes in the body. However, little is known about the function of these compounds in the central nervous system. Endogenous cardiotonic steroids are involved in the pathogenesis of affective disorders, including depression and bipolar disorder, which are linked to dopaminergic system dysfunction. Animal models have shown that the cardiotonic steroid ouabain induces mania-like behavior through dopamine-dependent intracellular signaling pathways. In addition, mutations in the alpha subunit of Na+,K+-ATPase lead to the development of neurological pathologies. Evidence from animal models confirms the neurological consequences of mutations in the Na+,K+-ATPase alpha subunit. This review is dedicated to discussing the role of cardiotonic steroids and Na+,K+-ATPase in dopaminergic system pathologies—both the evidence supporting their involvement and potential pathways along which they may exert their effects are evaluated. Since there is an association between affective disorders accompanied by functional alterations in the dopaminergic system and neurological disorders such as Parkinson’s disease, we extend our discussion to the role of Na+,K+-ATPase and cardiotonic steroids in neurodegenerative diseases as well. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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42 pages, 2955 KiB  
Systematic Review
Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal
by Felice Iasevoli, Camilla Avagliano, Luigi D’Ambrosio, Annarita Barone, Mariateresa Ciccarelli, Giuseppe De Simone, Benedetta Mazza, Licia Vellucci and Andrea de Bartolomeis
Biomedicines 2023, 11(3), 895; https://doi.org/10.3390/biomedicines11030895 - 14 Mar 2023
Cited by 5 | Viewed by 2790
Abstract
Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates [...] Read more.
Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates in the neurobiology of antipsychotic non-response, although other neurotransmitter systems play a role. The aims of this review are: (i) to recapitulate and critically appraise the relevant literature on dopamine-related mechanisms of TRS; (ii) to discuss the methodological limitations of the studies so far conducted and delineate a theoretical framework on dopamine mechanisms of TRS; and (iii) to highlight future perspectives of research and unmet needs. Dopamine-related neurobiological mechanisms of TRS may be multiple and putatively subdivided into three biological points: (1) D2R-related, including increased D2R levels; increased density of D2Rs in the high-affinity state; aberrant D2R dimer or heteromer formation; imbalance between D2R short and long variants; extrastriatal D2Rs; (2) presynaptic dopamine, including low or normal dopamine synthesis and/or release compared to responder patients; and (3) exaggerated postsynaptic D2R-mediated neurotransmission. Future points to be addressed are: (i) a more neurobiologically-oriented phenotypic categorization of TRS; (ii) implementation of neurobiological studies by directly comparing treatment resistant vs. treatment responder patients; (iii) development of a reliable animal model of non-response to antipsychotics. Full article
(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)
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