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The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 January 2024) | Viewed by 8516

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Special Issue Editor

Prof. Dr. Yingfang Tian

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Guest Editor

College of Life Sciences, Shaanxi Normal University, Xi'an 710062, China
Interests: neural mechanism of autism; neural mechanism of reinforcement learning

Special Issue Information

Dear Colleagues,

Dopamine is one of the most important catecholamine neurotransmitters in the central nervous system and plays an important role in regulating many functions of the brain, such as motor, cognition, emotion, positive reinforcement, feeding and endocrine functions. Dopamine is closely related to the pathogenesis of neurological diseases such as Parkinson's disease, schizophrenia, Tourette's syndrome, drug addiction, learning and memory deficits, and attention deficit hyperactivity syndrome. Among them, schizophrenia is mainly related to dopamine dysfunction, and treatments targeting the central nervous system dopamine pathway have also been developed. Most frequently used antipsychotics primarily reduce the level of dopamine activity.

Prof. Dr. Yingfang Tian
Guest Editor

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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.

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Published Papers (7 papers)

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Research

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22 pages, 3481 KiB

Open AccessArticle

The Dopaminergic Cells in the Median Raphe Region Regulate Social Behavior in Male Mice

by Tiago Chaves, Bibiána Török, Csilla Lea Fazekas, Pedro Correia, Eszter Sipos, Dorottya Várkonyi, Zsuzsanna E. Tóth, Fanni Dóra, Árpád Dobolyi and Dóra Zelena

Int. J. Mol. Sci. 2024, 25(8), 4315; https://doi.org/10.3390/ijms25084315 - 13 Apr 2024

Viewed by 493

Abstract

According to previous studies, the median raphe region (MRR) is known to contribute significantly to social behavior. Besides serotonin, there have also been reports of a small population of dopaminergic neurons in this region. Dopamine is linked to reward and locomotion, but very little is known about its role in the MRR. To address that, we first confirmed the presence of dopaminergic cells in the MRR of mice (immunohistochemistry, RT-PCR), and then also in humans (RT-PCR) using healthy donor samples to prove translational relevance. Next, we used chemogenetic technology in mice containing the Cre enzyme under the promoter of the dopamine transporter. With the help of an adeno-associated virus, designer receptors exclusively activated by designer drugs (DREADDs) were expressed in the dopaminergic cells of the MRR to manipulate their activity. Four weeks later, we performed an extensive behavioral characterization 30 min after the injection of the artificial ligand (Clozapine-N-Oxide). Stimulation of the dopaminergic cells in the MRR decreased social interest without influencing aggression and with an increase in social discrimination. Additionally, inhibition of the same cells increased the friendly social behavior during social interaction test. No behavioral changes were detected in anxiety, memory or locomotion. All in all, dopaminergic cells were present in both the mouse and human samples from the MRR, and the manipulation of the dopaminergic neurons in the MRR elicited a specific social response. Full article

(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)

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22 pages, 2471 KiB

Open AccessArticle

Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution

by Iva Spreitzer, Josefin Keife, Tobias Strasser, Predrag Kalaba, Jana Lubec, Winfried Neuhaus, Gert Lubec, Thierry Langer, Judith Wackerlig and Irena Loryan

Int. J. Mol. Sci. 2023, 24(23), 16956; https://doi.org/10.3390/ijms242316956 - 29 Nov 2023

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Abstract

S-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of S-CE-123 and R-modafinil. To address this objective, a precise liquid chromatography–high resolution mass spectrometry method was developed and partially validated. Neuropharmacokinetic parameters were assessed using the Combinatory Mapping Approach. Our findings reveal distinct differences between the two compounds. Notably, S-CE-123 demonstrates a significantly superior extent of transport across the blood–brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (K_p,uu,brain) of 0.5, compared to R-modafinil’s K_p,uu,brain of 0.1. A similar pattern was observed for the transport across the blood–spinal cord barrier. Concerning the drug transport across cellular membranes, we observed that S-CE-123 primarily localizes in the brain interstitial space, whereas R-modafinil distributes more evenly across both sides of the plasma membrane of the brain’s parenchymal cells (K_p,uu,cell). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with S-CE-123 having a 9.3-fold faster metabolism compared to R-modafinil. In summary, the combination of improved BBB transport and higher affinity of S-CE-123 to dopamine transporters in comparison to R-modafinil makes S-CE-123 a promising candidate for further testing for the treatment of cognitive decline. Full article

(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)

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13 pages, 2113 KiB

Open AccessArticle

Influence of Inflammatory Pain and Dopamine on Synaptic Transmission in the Mouse ACC

by Soroush Darvish-Ghane, Jennet Baumbach and Loren J. Martin

Int. J. Mol. Sci. 2023, 24(13), 11113; https://doi.org/10.3390/ijms241311113 - 5 Jul 2023

Cited by 1 | Viewed by 1171

Abstract

Dopamine (DA) inhibits excitatory synaptic transmission in the anterior cingulate cortex (ACC), a brain region involved in the sensory and affective processing of pain. However, the DA modulation of inhibitory synaptic transmission in the ACC and its alteration of the excitatory/inhibitory (E/I) balance remains relatively understudied. Using patch-clamp recordings, we demonstrate that neither DA applied directly to the tissue slice nor complete Freund’s adjuvant (CFA) injected into the hind paw significantly impacted excitatory currents (eEPSCs) in the ACC, when recorded without pharmacological isolation. However, individual neurons exhibited varied responses to DA, with some showing inhibition, potentiation, or no response. The degree of eEPSC inhibition by DA was higher in naïve slices compared to that in the CFA condition. The baseline inhibitory currents (eIPSCs) were greater in the CFA-treated slices, and DA specifically inhibited eIPSCs in the CFA-treated, but not naïve group. DA and CFA treatment did not alter the balance between excitatory and inhibitory currents. Spontaneous synaptic activity revealed that DA reduced the frequency of the excitatory currents in CFA-treated mice and decreased the amplitude of the inhibitory currents, specifically in CFA-treated mice. However, the overall synaptic drive remained similar between the naïve and CFA-treated mice. Additionally, GABAergic currents were pharmacologically isolated and found to be robustly inhibited by DA through postsynaptic D2 receptors and G-protein activity. Overall, the study suggests that CFA-induced inflammation and DA do not significantly affect the balance between excitatory and inhibitory currents in ACC neurons, but activity-dependent changes may be observed in the DA modulation of presynaptic glutamate release in the presence of inflammation. Full article

(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)

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19 pages, 27320 KiB

Open AccessArticle

Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor

by Wenbin Jia, Ichiro Kawahata, An Cheng, Takuya Sasaki, Toshikuni Sasaoka and Kohji Fukunaga

Int. J. Mol. Sci. 2023, 24(7), 6644; https://doi.org/10.3390/ijms24076644 - 2 Apr 2023

Cited by 2 | Viewed by 1631

Abstract

We previously demonstrated that fatty acid-binding protein 3 null (FABP3^−/−) mice exhibit resistance to nicotine-induced conditioned place preference (CPP). Here, we confirm that the FABP3 inhibitor, MF1 ((4-(2-(1-(2-chlorophenyl)-5-phenyl-1H-pyrazol-3-yl)phenoxy) butanoic acid), successfully reduces nicotine-induced CPP scores in mice. MF1 (0.3 or 1.0 mg/kg) was orally administered 30 min before nicotine, and CPP scores were assessed in the conditioning, withdrawal, and relapse phases. MF1 treatment decreased CPP scores in a dose-dependent manner. Failure of CPP induction by MF1 (1.0 mg/kg, p.o.) was associated with the inhibition of both CaMKII and ERK activation in the nucleus accumbens (NAc) and hippocampal CA1 regions. MF1 treatment reduced nicotine-induced increases in phosphorylated CaMKII and cAMP-response element-binding protein (CREB)-positive cells. Importantly, the increase in dopamine D2 receptor (D2R) levels following chronic nicotine exposure was inhibited by MF1 treatment. Moreover, the quinpirole (QNP)-induced increase in the level of CaMKII and ERK phosphorylation was significantly inhibited by MF1 treatment of cultured NAc slices from wild type (WT) mice; however, QNP treatment had no effect on CaMKII and ERK phosphorylation levels in the NAc of D2R null mice. Taken together, these results show that MF1 treatment suppressed D2R/FABP3 signaling, thereby preventing nicotine-induced CPP induction. Hence, MF1 can be used as a novel drug to block addiction to nicotine and other drugs by inhibiting the dopaminergic system. Full article

(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)

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Review

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16 pages, 1922 KiB

Open AccessReview

Tyrosine Hydroxylase Inhibitors and Dopamine Receptor Agonists Combination Therapy for Parkinson’s Disease

by Ling Xiao Yi, Eng King Tan and Zhi Dong Zhou

Int. J. Mol. Sci. 2024, 25(9), 4643; https://doi.org/10.3390/ijms25094643 - 24 Apr 2024

Viewed by 404

Abstract

There are currently no disease-modifying therapies for Parkinson’s disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients’ brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression. Full article

(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)

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28 pages, 1913 KiB

Open AccessReview

Inflammation, Dopaminergic Brain and Bilirubin

by Sri Jayanti, Camilla Dalla Verde, Claudio Tiribelli and Silvia Gazzin

Int. J. Mol. Sci. 2023, 24(14), 11478; https://doi.org/10.3390/ijms241411478 - 14 Jul 2023

Cited by 3 | Viewed by 2639

Abstract

Dopamine is a well-known neurotransmitter due to its involvement in Parkinson’s disease (PD). Dopamine is not only involved in PD but also controls multiple mental and physical activities, such as the pleasure of food, friends and loved ones, music, art, mood, cognition, motivation, fear, affective disorders, addiction, attention deficit disorder, depression, and schizophrenia. Dopaminergic neurons (DOPAn) are susceptible to stressors, and inflammation is a recognized risk for neuronal malfunctioning and cell death in major neurodegenerative diseases. Less is known for non-neurodegenerative conditions. Among the endogenous defenses, bilirubin, a heme metabolite, has been shown to possess important anti-inflammatory activity and, most importantly, to prevent DOPAn demise in an ex vivo model of PD by acting on the tumor necrosis factor-alpha (TNFα). This review summarizes the evidence linking DOPAn, inflammation (when possible, specifically TNFα), and bilirubin as an anti-inflammatory in order to understand what is known, the gaps that need filling, and the hypotheses of anti-inflammatory strategies to preserve dopamine homeostasis with bilirubin included. Full article

(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)

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Other

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15 pages, 1493 KiB

Open AccessPerspective

Dopamine Pharmacodynamics: New Insights

by Fulvio Lauretani, Francesco Giallauria, Crescenzo Testa, Claudia Zinni, Beatrice Lorenzi, Irene Zucchini, Marco Salvi, Raffaele Napoli and Marcello Giuseppe Maggio

Int. J. Mol. Sci. 2024, 25(10), 5293; https://doi.org/10.3390/ijms25105293 - 13 May 2024

Viewed by 182

Abstract

Dopamine is a key neurotransmitter involved in physiological processes such as motor control, motivation, reward, cognitive function, and maternal and reproductive behaviors. Therefore, dysfunctions of the dopaminergic system are related to a plethora of human diseases. Dopamine, via different circuitries implicated in compulsive behavior, reward, and habit formation, also represents a key player in substance use disorder and the formation and perpetuation of mechanisms leading to addiction. Here, we propose dopamine as a model not only of neurotransmission but also of neuromodulation capable of modifying neuronal architecture. Abuse of substances like methamphetamine, cocaine, and alcohol and their consumption over time can induce changes in neuronal activities. These modifications lead to synaptic plasticity and finally to morphological and functional changes, starting from maladaptive neuro-modulation and ending in neurodegeneration. Full article

(This article belongs to the Special Issue The Role of Dopamine Neurotransmitters in Neurological Diseases: New Sight)

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