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      5-Hydroxytryptamine Receptors and Tardive Dyskinesia in Schizophrenia

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          Tardive dyskinesia (TD) is a common side effect of antipsychotic treatment. This movement disorder consists of orofacial and limb-truncal components. The present study is aimed at investigating the role of serotonin receptors (HTR) in modulating tardive dyskinesia by genotyping patients with schizophrenia.


          A set of 29 SNPs of genes of serotonin receptors HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B, and HTR6 was studied in a population of 449 Caucasians (226 females and 223 males) with verified clinical diagnosis of schizophrenia (according to ICD-10: F20). Five SNPs were excluded because of low minor allele frequency or for not passing the Hardy-Weinberg equilibrium test. Affinity of antipsychotics to 5-HT2 receptors was defined according to previous publications. Genotyping was carried out with SEQUENOM Mass Array Analyzer 4.


          Statistically significant associations of rs1928040 of HTR2A gene in groups of patients with orofacial type of TD and total diagnosis of TD was found for alleles, and a statistical trend for genotypes. Moreover, statistically significant associations were discovered in the female group for rs1801412 of HTR2C for alleles and genotypes. Excluding patients who used HTR2A, respectively, HTR2C antagonists changed little to the associations of HTR2A polymorphisms, but caused a major change of the magnitude of the association of HTR2C variants. Due to the low patient numbers, these sub-analyses did not have significant results.


          We found significant associations in rs1928040 of HTR2A and for rs1801412 of X-bound HTR2C in female patients. The associations were particularly related to the orofacial type of TD. Excluding patients using relevant antagonists particularly affected rs1801412, but not rs1928040-related associations. This suggest that rs1801412 is directly or indirectly linked to the functioning of HTR2C. Further study of variants of the HTR2C gene in a larger group of male patients who were not using HTR2C antagonists is necessary in order to verify a possible functional role of this receptor.

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          Most cited references 37

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          Molecular biology of 5-HT receptors.

          Serotonin (5-hydroxytryptamine; 5-HT) is a monoamine neurotransmitter whose effects are mediated by at least 13 distinct G protein-coupled receptors (GPCRs) of the type A family which includes the monoamine receptors and a combination of ligand-gated ion channels (5-HT3) of the Cys loop family which constitutes heteropentamers. 5-HT receptors are currently divided into seven classes (5-HT1 to 5-HT7), based on structural, transductional and operational features. While this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity is supported by the existence of a great number of splice and editing variants for several 5-HT receptors, their possible modulation by accessory proteins and chaperones, as well as their potential to form homo or heteromers both at the GPCR and at the ligand-gated channel level.
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            Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment.

            Depressive disorders account for a large and increasing global burden of disease. Although the condition of many patients improves with medication, only a minority experience full remission, and patients whose condition responds to one medication may not have a response to others. Individual variation in antidepressant treatment outcome is, at present, unpredictable but may have a partial genetic basis. We searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives for Depression (STAR*D) study and were prospectively assessed. In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. We detected significant and reproducible association between treatment outcome and a marker in HTR2A (P range 1 x 10(-6) to 3.7 x 10(-5) in the total sample). Other markers in HTR2A also showed evidence of association with treatment outcome in the total sample. HTR2A encodes the serotonin 2A receptor, which is downregulated by citalopram. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele. The A allele was over six times more frequent in white than in black participants, and treatment was less effective among black participants. The A allele may contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.
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              The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease.

              L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements, i.e., L-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways.

                Author and article information

                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                24 April 2020
                : 13
                1Mental Health Research Institute, Tomsk National Research Medical Center of the Russian Academy of Sciences , Tomsk, Russia
                2Department of Cytology and Genetics, National Research Tomsk State University , Tomsk, Russia
                3Division for Control and Diagnostics, School of Non-Destructive Testing and Security, National Research Tomsk Polytechnic University , Tomsk, Russia
                4Hospital, Siberian State Medical University , Tomsk, Russia
                5PharmacoTherapy, -Epidemiology and -Economics, Groningen Research Institute of Pharmacy, University of Groningen , Groningen, Netherlands
                6Policy Office for Quality and Innovation of Care (BZI), GGZ Westelijk Noord-Brabant , Halsteren, Netherlands
                7Department of Psychiatry, Addictology and Psychotherapy, Siberian State Medical University , Tomsk, Russia
                8Department of Psychotherapy and Psychological Counseling, National Research Tomsk State University , Tomsk, Russia
                9Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen , Groningen, Netherlands
                Author notes

                Edited by: Raul R. Gainetdinov, Saint Petersburg State University, Russia

                Reviewed by: Jong-Woo Sohn, Korea Advanced Institute of Science and Technology, South Korea; Rosario Moratalla, Consejo Superior de Investigaciones Científicas (CSIC), Spain

                *Correspondence: Anton J. M. Loonen, a.j.m.loonen@ 123456rug.nl
                Copyright © 2020 Pozhidaev, Paderina, Fedorenko, Kornetova, Semke, Loonen, Bokhan, Wilffert and Ivanova.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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                Figures: 0, Tables: 4, Equations: 0, References: 39, Pages: 8, Words: 0
                Original Research


                schizophrenia, tardive dyskinesia, 5-ht receptors, pharmacogenetics, gene polymorphisms


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