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Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases

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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 (31 December 2023) | Viewed by 15426

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Special Issue Editors

Dr. Dorota Łażewska

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Guest Editor

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

Dr. Anna Stasiak

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Guest Editor

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

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

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

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 (11 papers)

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Research

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14 pages, 2821 KiB

Open AccessArticle

Effects of Bradykinin B2 Receptor Ablation from Tyrosine Hydroxylase Cells on Behavioral and Motor Aspects in Male and Female Mice

by Thaina Maquedo Franco, Mariana R. Tavares, Leonardo S. Novaes, Carolina D. Munhoz, Jose Eduardo Peixoto-Santos, Ronaldo C. Araujo, Jose Donato, Jr., Michael Bader and Frederick Wasinski

Int. J. Mol. Sci. 2024, 25(3), 1490; https://doi.org/10.3390/ijms25031490 - 25 Jan 2024

Viewed by 688

Abstract

The kallikrein–kinin system is a versatile regulatory network implicated in various biological processes encompassing inflammation, nociception, blood pressure control, and central nervous system functions. Its physiological impact is mediated through G-protein-coupled transmembrane receptors, specifically the B1 and B2 receptors. Dopamine, a key catecholamine neurotransmitter widely distributed in the CNS, plays a crucial role in diverse physiological functions including motricity, reward, anxiety, fear, feeding, sleep, and arousal. Notably, the potential physical interaction between bradykinin and dopaminergic receptors has been previously documented. In this study, we aimed to explore whether B2R modulation in catecholaminergic neurons influences the dopaminergic pathway, impacting behavioral, metabolic, and motor aspects in both male and female mice. B2R ablation in tyrosine hydroxylase cells reduced the body weight and lean mass without affecting body adiposity, substrate oxidation, locomotor activity, glucose tolerance, or insulin sensitivity in mice. Moreover, a B2R deficiency in TH cells did not alter anxiety levels, exercise performance, or motor coordination in female and male mice. The concentrations of monoamines and their metabolites in the substantia nigra and cortex region were not affected in knockout mice. In essence, B2R deletion in TH cells selectively influenced the body weight and composition, leaving the behavioral and motor aspects largely unaffected. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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15 pages, 3110 KiB

Open AccessArticle

Dopamine D4 Receptor Agonist Drastically Increases Delta Activity in the Thalamic Nucleus Reuniens: Potential Role in Communication between Prefrontal Cortex and Hippocampus

by J. Kuang, V. Kafetzopoulos, Richard Deth and B. Kocsis

Int. J. Mol. Sci. 2023, 24(20), 15289; https://doi.org/10.3390/ijms242015289 - 18 Oct 2023

Viewed by 819

Abstract

Network oscillations are essential for all cognitive functions. Oscillatory deficits are well established in psychiatric diseases and are recapitulated in animal models. They are significantly and specifically affected by pharmacological interventions using psychoactive compounds. Dopamine D4 receptor (D4R) activation was shown to enhance gamma rhythm in freely moving rats and to specifically affect slow delta and theta oscillations in the urethane-anesthetized rat model. The goal of this study was to test the effect of D4R activation on slow network oscillations at delta and theta frequencies during wake states, potentially supporting enhanced functional connectivity during dopamine-induced attention and cognitive processing. Network activity was recorded in the prefrontal cortex (PFC), hippocampus (HC) and nucleus reuniens (RE) in control conditions and after injecting the D4R agonist A-412997 (3 and 5 mg/kg; systemic administration). We found that A-412997 elicited a lasting (~40 min) wake state and drastically enhanced narrow-band delta oscillations in the PFC and RE in a dose-dependent manner. It also preferentially enhanced delta synchrony over theta coupling within the PFC-RE-HC circuit, strongly strengthening PFC-RE coupling. Thus, our findings indicate that the D4R may contribute to cognitive processes, at least in part, through acting on wake delta oscillations and that the RE, providing an essential link between the PFC and HC, plays a prominent role in this mechanism. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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14 pages, 3219 KiB

Open AccessArticle

Whole-Body Vibration Prevents Neuronal, Neurochemical, and Behavioral Effects of Morphine Withdrawal in a Rat Model

by Gavin C. Jones, Christina A. Small, Dallin Z. Otteson, Caylor W. Hafen, Jacob T. Breinholt, Paul D. Flora, Matthew D. Burris, David W. Sant, Tysum R. Ruchti, Jordan T. Yorgason, Scott C. Steffensen and Kyle B. Bills

Int. J. Mol. Sci. 2023, 24(18), 14147; https://doi.org/10.3390/ijms241814147 - 15 Sep 2023

Cited by 1 | Viewed by 980

Abstract

Peripheral mechanoreceptor-based treatments such as acupuncture and chiropractic manipulation have shown success in modulating the mesolimbic dopamine (DA) system originating in the ventral tegmental area (VTA) of the midbrain and projecting to the nucleus accumbens (NAc) of the striatum. We have previously shown that mechanoreceptor activation via whole-body vibration (WBV) ameliorates neuronal and behavioral effects of chronic ethanol exposure. In this study, we employ a similar paradigm to assess the efficacy of WBV as a preventative measure of neuronal and behavioral effects of morphine withdrawal in a Wistar rat model. We demonstrate that concurrent administration of WBV at 80 Hz with morphine over a 5-day period significantly reduced adaptations in VTA GABA neuronal activity and NAc DA release and modulated expression of δ-opioid receptors (DORs) on NAc cholinergic interneurons (CINs) during withdrawal. We also observed a reduction in behavior typically associated with opioid withdrawal. WBV represents a promising adjunct to current intervention for opioid use disorder (OUD) and should be examined translationally in humans. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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17 pages, 2817 KiB

Open AccessArticle

The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3β Signaling Pathway in MK801-Induced Amnesia in Mice

by Sabna Abdalla, Nermin Eissa, Petrilla Jayaprakash, Rami Beiram, Kamil J. Kuder, Dorota Łażewska, Katarzyna Kieć-Kononowicz and Bassem Sadek

Int. J. Mol. Sci. 2023, 24(16), 12719; https://doi.org/10.3390/ijms241612719 - 12 Aug 2023

Cited by 1 | Viewed by 1227

Abstract

The role of histamine H3 receptors (H3Rs) in memory and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer’s disease (AD), is well-accepted. Therefore, the procognitive effects of acute systemic administration of H3R antagonist E169 (2.5–10 mg/kg, i.p.) on MK801-induced amnesia in C57BL/6J mice using the novel object recognition test (NORT) were evaluated. E169 (5 mg) provided a significant memory-improving effect on MK801-induced short- and long-term memory impairments in NORT. The E169 (5 mg)-provided effects were comparable to those observed with the reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and were abrogated with the H3R agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that E169 ameliorated MK801-induced memory deficits by antagonism of H3Rs and by modulation of the level of disturbance in the expression of PI3K, Akt, and GSK-3β proteins, signifying that E169 mitigated the Akt-mTOR signaling pathway in the hippocampus of tested mice. Moreover, the results observed revealed that E169 (2.5–10 mg/kg, i.p.) did not alter anxiety levels and locomotor activity of animals in open field tests, demonstrating that performances improved following acute systemic administration with E169 in NORT are unrelated to changes in emotional response or in spontaneous locomotor activity. In summary, these obtained results suggest the potential of H3R antagonists such as E169, with good in silico physicochemical properties and stable retained key interactions in docking studies at H3R, in simultaneously modulating disturbed brain neurotransmitters and the imbalanced Akt-mTOR signaling pathway related to neurodegenerative disorders, e.g., AD. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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14 pages, 2336 KiB

Open AccessArticle

Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats

by Sevag Hamamah, Andras Hajnal and Mihai Covasa

Int. J. Mol. Sci. 2023, 24(11), 9773; https://doi.org/10.3390/ijms24119773 - 05 Jun 2023

Cited by 1 | Viewed by 1096

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 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

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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13 pages, 1914 KiB

Open AccessArticle

Selective Activation of D3 Dopamine Receptors Ameliorates DOI-Induced Head Twitching Accompanied by Changes in Corticostriatal Processing

by Ana María Estrada-Sánchez, Claudia Rangel-Barajas, Andrew G. Howe, Scott J. Barton, Robert H. Mach, Robert R. Luedtke and George V. Rebec

Int. J. Mol. Sci. 2023, 24(11), 9300; https://doi.org/10.3390/ijms24119300 - 26 May 2023

Viewed by 1612

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 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

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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18 pages, 2417 KiB

Open AccessArticle

Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer’s Disease

by Stephanie M. Perez, Angela M. Boley, Alexandra M. McCoy and Daniel J. Lodge

Int. J. Mol. Sci. 2023, 24(8), 7196; https://doi.org/10.3390/ijms24087196 - 13 Apr 2023

Cited by 4 | Viewed by 1585

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 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

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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27 pages, 9776 KiB

Open AccessArticle

Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D₃-Selective Antagonists

by Ho Young Kim, Ji Youn Lee, Chia-Ju Hsieh, Michelle Taylor, Robert R. Luedtke and Robert H. Mach

Int. J. Mol. Sci. 2023, 24(1), 432; https://doi.org/10.3390/ijms24010432 - 27 Dec 2022

Cited by 5 | Viewed by 1918

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 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

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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Review

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23 pages, 1236 KiB

Open AccessReview

Dopamine Signaling in Substantia Nigra and Its Impact on Locomotor Function—Not a New Concept, but Neglected Reality

by Michael F. Salvatore

Int. J. Mol. Sci. 2024, 25(2), 1131; https://doi.org/10.3390/ijms25021131 - 17 Jan 2024

Cited by 1 | Viewed by 1079

Abstract

The mechanistic influences of dopamine (DA) signaling and impact on motor function are nearly always interpreted from changes in nigrostriatal neuron terminals in striatum. This is a standard practice in studies of human Parkinson’s disease (PD) and aging and related animal models of PD and aging-related parkinsonism. However, despite dozens of studies indicating an ambiguous relationship between changes in striatal DA signaling and motor phenotype, this perseverating focus on striatum continues. Although DA release in substantia nigra (SN) was first reported almost 50 years ago, assessment of nigral DA signaling changes in relation to motor function is rarely considered. Whereas DA signaling has been well-characterized in striatum at all five steps of neurotransmission (biosynthesis and turnover, storage, release, reuptake, and post-synaptic binding) in the nigrostriatal pathway, the depth of such interrogations in the SN, outside of cell counts, is sparse. However, there is sufficient evidence that these steps in DA neurotransmission in the SN are operational and regulated autonomously from striatum and are present in human PD and aging and related animal models. To complete our understanding of how nigrostriatal DA signaling affects motor function, it is past time to include interrogation of nigral DA signaling. This brief review highlights evidence that changes in nigral DA signaling at each step in DA neurotransmission are autonomous from those in striatum and changes in the SN alone can influence locomotor function. Accordingly, for full characterization of how nigrostriatal DA signaling affects locomotor activity, interrogation of DA signaling in SN is essential. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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15 pages, 7046 KiB

Open AccessReview

Current Review of the Function and Regulation of Tuberoinfundibular Dopamine Neurons

by Xiaojun Qi-Lytle, Sarah Sayers and Edward J. Wagner

Int. J. Mol. Sci. 2024, 25(1), 110; https://doi.org/10.3390/ijms25010110 (registering DOI) - 21 Dec 2023

Cited by 1 | Viewed by 954

Abstract

Tuberoinfundibular dopamine (TIDA) neurons have cell bodies located in the arcuate nucleus of the mediobasal hypothalamus. They project to the external zone of the median eminence, and the dopamine (DA) released there is carried by the hypophysial portal vasculature to the anterior pituitary. The DA then activates D2 receptors to inhibit prolactin (PRL) secretion from lactotrophs. The TIDA neuronal population is the principal regulatory factor controlling PRL secretion. The neuroendocrine role subserved by TIDA neurons sets them apart from other dopaminergic populations like the nigrostriatal and mesolimbic DA neurons. TIDA neurons exhibit intrinsic oscillatory fluctuations in their membrane potential that give rise to phasic firing and bursting activity. TIDA neuronal activity is sexually differentiated and modulated by gonadal hormones and PRL, as well as an array of small molecule and peptide neurotransmitters. This review covers these characteristics. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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20 pages, 583 KiB

Open AccessReview

Implications of Physical Exercise on Episodic Memory and Anxiety: The Role of the Serotonergic System

by Ricardo Illesca-Matus, Nicolás M. Ardiles, Felipe Munoz and Pablo R. Moya

Int. J. Mol. Sci. 2023, 24(14), 11372; https://doi.org/10.3390/ijms241411372 - 12 Jul 2023

Cited by 2 | Viewed by 2052

Abstract

There is a growing interest in investigating the effects of physical exercise on cognitive performance, particularly episodic memory. Similarly, an increasing number of studies in recent decades have studied the effects of physical activity on mood and anxiety disorders. Moreover, the COVID-19 pandemic has raised awareness of the importance of regular physical activity for both mental and physical health. Nevertheless, the exact mechanisms underlying these effects are not fully understood. Interestingly, recent findings suggest that the serotonergic system may play a key role in mediating the effects of physical exercise on episodic memory and anxiety. In this review, we discuss the impact of physical exercise on both episodic memory and anxiety in human and animal models. In addition, we explore the accumulating evidence that supports a role for the serotonergic system in the effects of physical exercise on episodic memory and anxiety. Full article

(This article belongs to the Special Issue Dopamine, Histamine, Serotonin—Receptors, Ligands and Their Biological Role in Central Nervous System Diseases)

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