Biomedicines

Research

18 pages, 3144 KiB

Open AccessArticle

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 1264

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

Open AccessArticle

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 2568

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

Open AccessArticle

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 1579

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

Open AccessArticle

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 1403

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

Open AccessArticle

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 1290

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

Open AccessArticle

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 1414

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

Open AccessArticle

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 2182

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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17 pages, 1605 KiB

Open AccessReview

The Effects of Chronic Psychostimulant Administration on Bone Health: A Review

by Jessica Nowak, Jacob Aronin, Faraaz Beg, Natasha O’Malley, Michael Ferrick, Teresa Quattrin, Sonja Pavlesen, Michael Hadjiargyrou, David E. Komatsu and Panayotis K. Thanos

Biomedicines 2024, 12(8), 1914; https://doi.org/10.3390/biomedicines12081914 - 21 Aug 2024

Viewed by 809

Abstract

(1) Background: Methylphenidate (MP) and amphetamine (AMP) are psychostimulants that are widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. In recent years, 6.1 million children received an ADHD diagnosis, and nearly 2/3 of these children were prescribed psychostimulants for treatment. [...] Read more.

(1) Background: Methylphenidate (MP) and amphetamine (AMP) are psychostimulants that are widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy. In recent years, 6.1 million children received an ADHD diagnosis, and nearly 2/3 of these children were prescribed psychostimulants for treatment. The purpose of this review is to summarize the current literature on psychostimulant use and the resulting effects on bone homeostasis, biomechanical properties, and functional integrity. (2) Methods: Literature searches were conducted from Medline/PubMed electronic databases utilizing the search terms “methylphenidate” OR “amphetamine” OR “methylphenidate” AND “bone health” AND “bone remodeling” AND “osteoclast” AND “osteoblast” AND “dopamine” from 01/1985 to 04/2023. (3) Results: Of the 550 publications found, 44 met the inclusion criteria. Data from identified studies demonstrate that the use of MP and AMP results in decreases in specific bone properties and biomechanical integrity via downstream effects on osteoblasts and osteoclast-related genes. (4) Conclusions: The chronic use of psychostimulants negatively affects bone integrity and strength as a result of increased osteoclast activity. These data support the need to take this into consideration when planning the treatment type and duration for bone fractures. Full article

(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)

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16 pages, 2690 KiB

Open AccessReview

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

Cited by 1 | Viewed by 1285

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

(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)

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34 pages, 827 KiB

Open AccessReview

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 5 | Viewed by 8231

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

Open AccessReview

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

Cited by 4 | Viewed by 12687

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

(This article belongs to the Special Issue Dopamine Signaling Pathway in Health and Disease)

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15 pages, 1036 KiB

Open AccessReview

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 5 | Viewed by 4071

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

Open AccessReview

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 1576

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

Open AccessSystematic 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 3801

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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