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Special Issue "Dopamine, Histamine, Serotonin – Receptors, Ligands and Their Biological Role in Central Nervous System Diseases"

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: 31 December 2023 | Viewed by 2804

Special Issue Editors

Chair of Technology and Biotechnology of Medical Remedies, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, ul. Medyczna 9, 30-688 Kraków, Poland
Interests: medicinal chemistry; multitarget ligands; drug design; synthesis; neurodegenerative disorders; histamine H3 receptors
Special Issues, Collections and Topics in MDPI journals
Department of Hormone Biochemistry, Medical University of Lodz, Żeligowskiego Street 7/9, 90-752 Łódź, Poland
Interests: neurochemistry; neurotransmitter dysregulation; histamine receptors; neurodegenerative diseases; multi-targeting drugs; experimental animal models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The human brain, with its network of neurotransmitters, is still an intriguing mystery to us. Neurotransmitters direct the work of the entire brain, transmitting important information and influencing important vital functions.

Dopamine and serotonin are some of the most important neurotransmitters in our brain. The role of histamine is equally important in the sleep-wake cycle or in processes related to memory and concentration. Each of these amines, acting through their receptors, influences many important vital functions and plays an important role in the onset and course of many CNS diseases.

An in-depth knowledge and understanding of the mechanisms of these diseases onset and progression, especially those with an important role for dopamine, histamine or serotonin, can help identify early symptoms of them, and introduction of a proper therapy.

Papers on these amines, their receptors and ligands are encourage. Particularly works involving the search for new active compounds, especially those with multitargeting activity, and their pharmacological or pharmacokinetic evaluation. All preclinical studies (including in vitro, ex vivo and in vivo studies) related to effects via dopamine, histamine or serotonin are welcome.

Dr. Dorota Łażewska
Dr. Anna Stasiak
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • biogenic amines (histamine, dopamine, serotonin)
  • receptors
  • ligands
  • antagonist/inverse agonist
  • affinity
  • intrinsic activity
  • multitarget ligands
  • molecular modeling
  • CNS diseases
  • neurodegeneration
  • psychiatric disorders
  • pain
  • in vitro studies
  • in silico studies
  • in vivo studies

Published Papers (4 papers)

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Research

Article
Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats
Int. J. Mol. Sci. 2023, 24(11), 9773; https://doi.org/10.3390/ijms24119773 - 05 Jun 2023
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Abstract
Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control [...] Read more.
Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control Long-Evans Tokushima (LETO) rats, OLETF rats have pronounced avidity for over-consuming palatable sweet solutions, have greater dopamine release to psychostimulants, reduced dopamine 2 receptor (D2R) binding, and exhibit increased sensitivity to sucrose reward. This supports altered dopamine function in this strain and its general preference for palatable solutions such as sucrose. In this study, we examined the relationship between OLETF’s hyperphagic behavior and striatal dopamine signaling by investigating basal and amphetamine stimulated motor activity in prediabetic OLETF rats before and after access to sucrose solution (0.3 M) compared to non-mutant control LETO rats, as well as availability of dopamine transporter (DAT) using autoradiography. In the sucrose tests, one group of OLETF rats received ad libitum access to sucrose while the other group received an amount of sucrose equal to that consumed by the LETO. OLETFs with ad libitum access consumed significantly more sucrose than LETOs. Sucrose exerted a biphasic effect on basal activity in both strains, i.e., reduced activity for 1 week followed by increased activity in weeks 2 and 3. Basal locomotor activity was reduced (−17%) in OLETFs prior to sucrose, compared to LETOs. Withdrawal of sucrose resulted in increased locomotor activity in both strains. The magnitude of this effect was greater in OLETFs and the activity was increased in restricted compared to ad-libitum-access OLETFs. Sucrose access augmented AMPH-responses in both strains with a greater sensitization to AMPH during week 1, an effect that was a function of the amount of sucrose consumed. One week of sucrose withdrawal sensitized AMPH-induced ambulatory activity in both strains. In OLETF with restricted access to sucrose, withdrawal resulted in no further sensitization to AMPH. DAT availability in the nucleus accumbens shell was significantly reduced in OLETF compared with aged-matched LETO. Together, these findings show that OLETF rats have reduced basal DA transmission and a heightened response to natural and pharmacological stimulation. Full article
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Article
Selective Activation of D3 Dopamine Receptors Ameliorates DOI-Induced Head Twitching Accompanied by Changes in Corticostriatal Processing
Int. J. Mol. Sci. 2023, 24(11), 9300; https://doi.org/10.3390/ijms24119300 - 26 May 2023
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Abstract
D3 receptors, a key component of the dopamine system, have emerged as a potential target of therapies to improve motor symptoms across neurodegenerative and neuropsychiatric conditions. In the present work, we evaluated the effect of D3 receptor activation on the involuntary head twitches [...] Read more.
D3 receptors, a key component of the dopamine system, have emerged as a potential target of therapies to improve motor symptoms across neurodegenerative and neuropsychiatric conditions. In the present work, we evaluated the effect of D3 receptor activation on the involuntary head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) at behavioral and electrophysiological levels. Mice received an intraperitoneal injection of either a full D3 agonist, WC 44 [4-(2-fluoroethyl)-N-[4-[4-(2-methoxyphenyl)piperazin 1-yl]butyl]benzamide] or a partial D3 agonist, WW-III-55 [N-(4-(4-(4-methoxyphenyl)piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide] five minutes before the intraperitoneal administration of DOI. Compared to the control group, both D3 agonists delayed the onset of the DOI-induced head-twitch response and reduced the total number and frequency of the head twitches. Moreover, the simultaneous recording of neuronal activity in the motor cortex (M1) and dorsal striatum (DS) indicated that D3 activation led to slight changes in a single unit activity, mainly in DS, and increased its correlated firing in DS or between presumed cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs). Our results confirm the role of D3 receptor activation in controlling DOI-induced involuntary movements and suggest that this effect involves, at least in part, an increase in correlated corticostriatal activity. A further understanding of the underlying mechanisms may provide a suitable target for treating neuropathologies in which involuntary movements occur. Full article
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Article
Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer’s Disease
Int. J. Mol. Sci. 2023, 24(8), 7196; https://doi.org/10.3390/ijms24087196 - 13 Apr 2023
Viewed by 533
Abstract
Antipsychotics increase the risk of death in elderly patients with Alzheimer’s disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with [...] Read more.
Antipsychotics increase the risk of death in elderly patients with Alzheimer’s disease (AD). Thus, there is an immediate need for novel therapies to treat comorbid psychosis in AD. Psychosis has been attributed to a dysregulation of the dopamine system and is associated with aberrant regulation by the hippocampus. Given that the hippocampus is a key site of pathology in AD, we posit that aberrant regulation of the dopamine system may contribute to comorbid psychosis in AD. A ferrous amyloid buthionine (FAB) rodent model was used to model a sporadic form of AD. FAB rats displayed functional hippocampal alterations, which were accompanied by decreases in spontaneous, low-frequency oscillations and increases in the firing rates of putative pyramidal neurons. Additionally, FAB rats exhibited increases in dopamine neuron population activity and augmented responses to the locomotor-inducing effects of MK-801, as is consistent with rodent models of psychosis-like symptomatology. Further, working memory deficits in the Y-maze, consistent with an AD-like phenotype, were observed in FAB rats. These data suggest that the aberrant hippocampal activity observed in AD may contribute to dopamine-dependent psychosis, and that the FAB model may be useful for the investigation of comorbid psychosis related to AD. Understanding the pathophysiology that leads to comorbid psychosis in AD will ultimately lead to the discovery of novel targets for the treatment of this disease. Full article
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Article
Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D3-Selective Antagonists
Int. J. Mol. Sci. 2023, 24(1), 432; https://doi.org/10.3390/ijms24010432 - 27 Dec 2022
Cited by 1 | Viewed by 949
Abstract
Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for [...] Read more.
Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8–13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development. Full article
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