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Alvarez-Herrera S, Rosel Vales M, Pérez-Sánchez G, Becerril-Villanueva E, Flores-Medina Y, Maldonado-García JL, Saracco-Alvarez R, Escamilla R, Pavón L. Risperidone Decreases Expression of Serotonin Receptor-2A (5-HT2A) and Serotonin Transporter (SERT) but Not Dopamine Receptors and Dopamine Transporter (DAT) in PBMCs from Patients with Schizophrenia. Pharmaceuticals (Basel) 2024; 17:167. [PMID: 38399382 PMCID: PMC10892557 DOI: 10.3390/ph17020167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 02/25/2024] Open
Abstract
Dopamine and serotonin receptors and transporters play an essential role in the pathophysiology of schizophrenia; changes in their expression have been reported in neurons and leukocytes. Each antipsychotic induces a unique pattern in leukocyte function and phenotype. However, the use of polytherapy to treat schizophrenia makes it challenging to determine the specific effects of risperidone on peripheral blood mononuclear cells (PBMCs). The aim of this study was to evaluate the changes in the expression of D3, D5, DAT, 5-HT2A, and SERT in PBMCs from healthy volunteers (HV), drug-naive patients with schizophrenia (PWS), drug-free PWS, and PWS treated with risperidone for up to 40 weeks using quantitative PCR. Our study revealed elevated mRNA levels of D3, DAT, 5-HT2A, and SERT in unmedicated PWS. Treatment with risperidone led to a reduction only in the expression of 5-HT2A and SERT. Furthermore, we observed a moderate correlation between 5-HT2A expression and the positive and negative syndrome scale (PANSS), as well as SERT expression and PANSS scale. We also found a moderate correlation between 5-HT2A and SERT expression and the positive subscale. The duration of risperidone consumption had a significant negative correlation with the expression of 5-HT2A and SERT. Our study introduces the measurement of 5-HT2A and SERT expression in PBMCs as a useful parameter for assessing the response to risperidone in PWS.
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Affiliation(s)
- Samantha Alvarez-Herrera
- Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico; (S.A.-H.); (G.P.-S.); (E.B.-V.)
| | - Mauricio Rosel Vales
- Clínica de Esquizofrenia, Dirección de Servicios Clínicos, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico;
| | - Gilberto Pérez-Sánchez
- Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico; (S.A.-H.); (G.P.-S.); (E.B.-V.)
| | - Enrique Becerril-Villanueva
- Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico; (S.A.-H.); (G.P.-S.); (E.B.-V.)
| | - Yvonne Flores-Medina
- Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico; (Y.F.-M.); (R.S.-A.)
| | - José Luis Maldonado-García
- Departamemto de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
- Departamemto de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Ricardo Saracco-Alvarez
- Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico; (Y.F.-M.); (R.S.-A.)
| | - Raúl Escamilla
- Subdirección de Consulta Externa, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico;
| | - Lenin Pavón
- Laboratorio de Psicoinmunología, Dirección de Investigaciones en Neurociencias, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñíz, Mexico City 14370, Mexico; (S.A.-H.); (G.P.-S.); (E.B.-V.)
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Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, Gaskill PJ. Dopamine, Immunity, and Disease. Pharmacol Rev 2023; 75:62-158. [PMID: 36757901 PMCID: PMC9832385 DOI: 10.1124/pharmrev.122.000618] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022] Open
Abstract
The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson's disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. SIGNIFICANCE STATEMENT: Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.
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Affiliation(s)
- Breana Channer
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Stephanie M Matt
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Emily A Nickoloff-Bybel
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Vasiliki Pappa
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Yash Agarwal
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Jason Wickman
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
| | - Peter J Gaskill
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania (B.C., S.M.M., E.A.N-B., Y.A., J.W., P.J.G.); and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania (V.P.)
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Nazari S, Pourmand SM, Makki SM, Brand S, Vousooghi N. Potential biomarkers of addiction identified by real-time PCR in human peripheral blood lymphocytes: a narrative review. Biomark Med 2022; 16:739-758. [PMID: 35658670 DOI: 10.2217/bmm-2021-0291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Addiction-related neurobiological factors could be considered as potential biomarkers. The concentration of peripheral biomarkers in tissues like blood lymphocytes may mirror their brain levels. This review is focused on the mRNA expression of potential addiction biomarkers in human peripheral blood lymphocytes (PBLs). PubMed, EMBASE, Web of Science, Scopus and Google Scholar were searched using the keywords 'addiction', 'biomarker', 'peripheral blood lymphocyte', 'gene expression' and 'real-time PCR'. The results showed the alterations in the regulation of genes such as dopamine receptors, opioid receptors, NMDA receptors, cannabinoid receptors, α-synuclein, DYN, MAO-A, FosB and orexin-A as PBLs biomarkers in addiction stages. Such variations could also be found during abstinence and relapse. PBLs biomarkers may help in drug development and have clinical implications.
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Affiliation(s)
- Shahrzad Nazari
- Department of Neuroscience & Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 1417755469, Iran
| | - Seyed Mahmoud Pourmand
- Addiction Department, School of Behavioral Sciences & Mental Health (Tehran Institute of Psychiatry), Iran University of Medical Sciences, Tehran, 1445613111, Iran
| | - Seyed Mohammad Makki
- Department of Psychiatry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985717443, Iran
| | - Serge Brand
- Center for Affective-, Stress- and Sleep Disorders (ZASS), Psychiatric Clinics (UPK), University of Basel, Basel, 4002, Switzerland.,Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran.,Substance Abuse Prevention Research Center, Kermanshah University of Medical Sciences, Kermanshah, 6714869914, Iran.,Department of Sport, Exercise, and Health, Division of Sport Science and Psychosocial Health, University of Basel, Basel, 4052, Switzerland.,Department of Psychiatry, School of Medicine, Tehran University of Medical Sciences, Tehran, 1417466191, Iran
| | - Nasim Vousooghi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, 1417755469, Iran.,Research Center for Cognitive & Behavioral Sciences, Tehran University of Medical Sciences, Tehran, 13337159140, Iran.,Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, 1336616357, Iran
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The role of dopamine receptors in lymphocytes and their changes in schizophrenia. Brain Behav Immun Health 2021; 12:100199. [PMID: 34589732 PMCID: PMC8474470 DOI: 10.1016/j.bbih.2021.100199] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 12/21/2020] [Indexed: 11/22/2022] Open
Abstract
Dopamine and its 5 receptors, which are grouped into two families (D1-like and D2-like), modulate functions at a systemic level in both the central nervous system and periphery. The central nervous system and the immune system are the main adaptive systems, which participate in a continuous and functional crosstalk to guarantee homeostasis. On binding to its 5 dopamine receptors, dopamine acts as a co-regulator of the immune system, contributing to the interaction of the central nervous system and inflammatory events and as a source of communication between the different immune cells. Dopaminergic perturbations in the central nervous system are observed in several neurological and psychiatric disorders. Schizophrenia is one of the most common mental disorders with a poorly understood pathoaetiology that includes genetic and environmental components that promote alterations in the dopaminergic system. Interestingly, abnormalities in dopamine receptors expression in lymphocytes of schizophrenia patients have been reported, often significantly correlating with the severity of the psychotic illness. Here, we review the current literature regarding the dopaminergic system in human lymphocytes and its alterations in schizophrenia.
The existence of DA in the bloodstream suggests the presence of dopaminergic components that modulate functions at a systemic level; therefore, its effects are not limited to the CNS and the signalling in the neuronal dopaminergic system should be independent from that of the peripheral systems. The effects by DA-mediated activation of different DRs on immune cells show different sensitivities to DA, but binding profiles of DA on T cells are similar to those in neuronal membranes, suggesting receptors act similarly to those found in neurons. All DRs are expressed on the LYM membrane. However, more detailed information is required on the expression patterns of DR in immune cells in healthy conditions and in pathologies. DA has been observed to influence LYM functions acting in a variety of important processes, like cytokine secretion, cell adhesion, chemotaxis, and cytotoxicity. In human LYM, DA on D1-like receptors decreases oxidative metabolism and apoptosis, activates the selective secretion of IL-10 and TNFα, and facilitates NK cells. In contrast, most of the immunostimulatory DA effects on LYM depend on stimulation of D2-like receptors including activation, proliferation, differentiation, and suppression of NK cells. To date, an altered expression or signalling of neurotransmitter receptors is observed in immune cells during psychiatric disorders and, consequently, these cells also markedly respond to antipsychotics. Numerous technologies have been used in search of biomarkers for SCZ. However, after a century of studying SCZ their application in psychiatry remains rare and there are currently no validated biomarkers for the diagnosis and prognosis of patients with SCZ or the prediction of treatment efficacy.
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Wysokiński A, Kozłowska E, Szczepocka E, Łucka A, Agier J, Brzezińska-Błaszczyk E, Sobierajska K. Expression of Dopamine D 1-4 and Serotonin 5-HT 1A-3A Receptors in Blood Mononuclear Cells in Schizophrenia. Front Psychiatry 2021; 12:645081. [PMID: 33776821 PMCID: PMC7988204 DOI: 10.3389/fpsyt.2021.645081] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 02/17/2021] [Indexed: 11/14/2022] Open
Abstract
Introduction: The aim of this study was to determine the mRNA expression profile of dopamine D1, D2, D3, D4 and serotonin 5-HT1A, 5-HT2A, and 5-HT3A receptors in peripheral blood mononuclear cells (PBMCs) in schizophrenia and the in vitro effect of antipsychotics on the expression of these receptors in PBMCs of healthy subjects. Materials and Methods: Twenty-seven patients with schizophrenia and 29 healthy controls were recruited for the study. All study subjects underwent thorough clinical assessment, including anthropometric and body composition measurements. The expression of mRNA for dopamine D1-4 and serotonin 5-HT1A-3A receptors was measured using quantitative RT-PCR in peripheral blood mononuclear cells. In vitro mRNA and protein expression of these receptors was measured using quantitative RT-PCR and Western Blotting in PBMCs cultured with quetiapine, haloperidol, aripiprazole, risperidone, olanzapine or clozapine at IC50, half of IC50, and one-quarter of IC50 concentrations. Results: The key finding was that the schizophrenia group demonstrated significantly higher mRNA expression of D1, D2 and D4 receptors (p < 0.001), and significantly lower mRNA expression of 5-HT3A receptors (p < 0.01). After adjusting for smoking, the mRNA expression of D1 lost its significance, while that of D3, 5-HT1A, 5-HT2A became significant (all three were lower in the schizophrenia group). These receptors also demonstrated different ratios of mRNA expression in the schizophrenia group. The in vitro experiments showed that high concentrations of antipsychotics influenced the mRNA and protein expression of all studied receptors. Conclusion: Schizophrenia patients display a distinctive pattern of dopamine and serotonin receptor mRNA expression in blood mononuclear cells. This expression is little affected by antipsychotic treatment and it may therefore serve as a useful diagnostic biomarker for schizophrenia.
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Affiliation(s)
- Adam Wysokiński
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Elżbieta Kozłowska
- Department of Experimental Immunology, Medical University of Lodz, Lodz, Poland
| | - Ewa Szczepocka
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Anna Łucka
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz, Lodz, Poland
| | - Justyna Agier
- Department of Experimental Immunology, Medical University of Lodz, Lodz, Poland
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Tavakkolifard M, Vousooghi N, Mahboubi S, Golab F, Ejtemaei Mehr S, Zarrindast MR. Evaluation of the relationship between the gene expression level of orexin-1 receptor in the rat blood and prefrontal cortex, novelty-seeking, and proneness to methamphetamine dependence: A candidate biomarker. Peptides 2020; 131:170368. [PMID: 32668268 DOI: 10.1016/j.peptides.2020.170368] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/19/2020] [Accepted: 07/06/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND previous studies have suggested that methamphetamine (METH) abuse may affect orexin regulation. However, the data regarding the relationship between the current level of orexin and the vulnerability to METH abuse are minimal. Here, we have investigated the correlation between the gene expression level of the orexin-1 receptor (OX1R) in the rat prefrontal cortex (PFC) and blood lymphocytes and susceptibility to METH dependence and its impact on novelty-seeking behavior. METHODS male Wistar rats were first examined for novelty-seeking behavior by the novel object recognition test, and the expression level of OX1R in their blood lymphocytes was evaluated by real-time PCR. Then, the susceptibility to METH abuse was investigated by voluntary METH oral consumption test. According to the amounts of METH consumption, the animals were divided into two groups of METH preferring and non-preferring. Half of the rats in each group were sacrificed, and the level of OX1R in their blood lymphocytes and PFC tissue was measured. The other half were sacrificed for the same reason after two weeks of drug abstinence. RESULTS The indexes of novelty-seeking behavior were significantly higher in the METH- preferring group compared to the non-preferring animals. Furthermore, the expression level of OX1R in the blood lymphocytes and PFC in the preferring group was considerably higher than the non-preferring group. CONCLUSION Up-regulation of the mRNA expression level of OX1R in the lymphocytes and PFC may predict vulnerability to the METH consumption and novelty-seeking, which may serve as a potential biomarker for METH abuse.
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Affiliation(s)
- Mahnoosh Tavakkolifard
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Vousooghi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran; Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran.
| | - Sara Mahboubi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Golab
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shahram Ejtemaei Mehr
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zarrindast
- Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Cognitive Neuroscience, Institute for Cognitive Science Studies, Tehran, Iran.
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Stark T, Di Bartolomeo M, Di Marco R, Drazanova E, Platania CBM, Iannotti FA, Ruda-Kucerova J, D'Addario C, Kratka L, Pekarik V, Piscitelli F, Babinska Z, Fedotova J, Giurdanella G, Salomone S, Sulcova A, Bucolo C, Wotjak CT, Starcuk Z, Drago F, Mechoulam R, Di Marzo V, Micale V. Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment. Biochem Pharmacol 2020; 177:114004. [PMID: 32360362 DOI: 10.1016/j.bcp.2020.114004] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 04/24/2020] [Indexed: 12/16/2022]
Abstract
Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities. Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques. Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is highly conserved in GPCRs. In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.
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Affiliation(s)
- Tibor Stark
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; RG "Neuronal Plasticity", Max Planck Institute of Psychiatry, Munich, Germany
| | - Martina Di Bartolomeo
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Roberta Di Marco
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Eva Drazanova
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic; Institute of Scientific Instruments of the Czech Academy of Sciences, Brno, Czech Republic
| | | | - Fabio Arturo Iannotti
- Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Endocannabinoid Research Group, Naples, Italy
| | - Jana Ruda-Kucerova
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Claudio D'Addario
- Faculty of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Lucie Kratka
- Institute of Scientific Instruments of the Czech Academy of Sciences, Brno, Czech Republic
| | - Vladimir Pekarik
- Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Fabiana Piscitelli
- Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Endocannabinoid Research Group, Naples, Italy
| | - Zuzana Babinska
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Julia Fedotova
- International Research Centre "Biotechnologies of the Third Millennium", ITMO University, St. Petersburg, Russian Federation; Laboratory of Neuroendocrinology, I.P. Pavlov Institute of Physiology RASci., St. Petersburg, Russian Federation; Lobachevsky State University of Nizhny Novgorod, Institute of Biology and Biomedicine, Nizhny Novgorod, Russian Federation
| | - Giovanni Giurdanella
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Salvatore Salomone
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Alexandra Sulcova
- ICCI - International Cannabis and Cannabinoid Institute, Praha, Czech Republic
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Carsten T Wotjak
- RG "Neuronal Plasticity", Max Planck Institute of Psychiatry, Munich, Germany; Boehringer Ingelheim Pharma GmbH & KO KG, Germany
| | - Zenon Starcuk
- Institute of Scientific Instruments of the Czech Academy of Sciences, Brno, Czech Republic
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Raphael Mechoulam
- Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Vincenzo Di Marzo
- Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Endocannabinoid Research Group, Naples, Italy; Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health, Université Laval, Quebec City, Canada; Joint International Unit on Chemical and Biomolecular Research on the Microbiome and its Impact on Metabolic Health and Nutrition (UMI-MicroMeNu), Université Laval and Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy
| | - Vincenzo Micale
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy; National Institute of Mental Health, Klecany, Czech Republic.
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Santos-Toscano R, Ucha M, Borcel É, Ambrosio E, Higuera-Matas A. Maternal immune activation is associated with a lower number of dopamine receptor 3-expressing granulocytes with no alterations in cocaine reward, resistance to extinction or cue-induced reinstatement. Pharmacol Biochem Behav 2020; 193:172930. [PMID: 32294488 DOI: 10.1016/j.pbb.2020.172930] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 04/08/2020] [Accepted: 04/09/2020] [Indexed: 02/08/2023]
Abstract
There is evidence for increased rates of drug use among schizophrenic patients. However, the causality in this relationship remains unclear. In the present work, we use a maternal immune activation model to test whether animals at high risk of developing a schizophrenia-like condition are more prone to acquire cocaine self-administration, show enhanced sensitivity to the reinforcing actions of cocaine or if they are resistant to extinction or vulnerable to relapse. Also, given that D3 and CB2 receptor expression in immune cells is altered in patients with schizophrenia, we examined the populations of immune cells expressing these receptors. Pregnant rats were daily injected with lipopolysaccharide (LPS) (2 mg/kg s.c.) or saline during pregnancy, and we tested prepulse inhibition -PPI- in the offspring. After this, one group of rats was submitted to cocaine self-administration (0.5 mg/kg) under fixed and progressive ratio schedules, dose-response testing, extinction and cue-induced drug-seeking. Another group was sacrificed to study the immune blood cells by flow cytometry. While rats born to LPS-treated mothers showed impaired PPI, there were no differences in cocaine self-administration acquisition, responsiveness to dose shifts, extinction or cue-induced reinstatement. Finally, there were fewer D3R+ granulocytes in the LPS-offspring and an exciting trend for CB2R+ lymphocytes to be more abundant in LPS-exposed rats. Our results indicate that the higher prevalence of cocaine abuse among people with schizophrenia is not due to a pre-existing pathology and suggest that D3R+ granulocytes and possibly CB2R+ lymphocytes could be potential biomarkers of schizophrenia.
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Affiliation(s)
- Raquel Santos-Toscano
- Department of Psychobiology, School of Psychology, National University for Distance Learning (UNED), Madrid, Spain
| | - Marcos Ucha
- Department of Psychobiology, School of Psychology, National University for Distance Learning (UNED), Madrid, Spain
| | - Érika Borcel
- Department of Psychobiology, School of Psychology, National University for Distance Learning (UNED), Madrid, Spain
| | - Emilio Ambrosio
- Department of Psychobiology, School of Psychology, National University for Distance Learning (UNED), Madrid, Spain
| | - Alejandro Higuera-Matas
- Department of Psychobiology, School of Psychology, National University for Distance Learning (UNED), Madrid, Spain.
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Vidal PM, Pacheco R. The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia. Front Pharmacol 2020; 11:394. [PMID: 32296337 PMCID: PMC7137825 DOI: 10.3389/fphar.2020.00394] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 03/16/2020] [Indexed: 12/14/2022] Open
Abstract
Dopamine is one of the neurotransmitters whose transmission is altered in a number of neural pathways in the brain of schizophrenic patients. Current evidence indicates that these alterations involve hyperactive dopaminergic transmission in mesolimbic areas, striatum, and hippocampus, whereas hypoactive dopaminergic transmission has been reported in the prefrontal cortex of schizophrenic patients. Consequently, schizophrenia is associated with several cognitive and behavioral alterations. Of note, the immune system has been found to collaborate with the central nervous system in a number of cognitive and behavioral functions, which are dysregulated in schizophrenia. Moreover, emerging evidence has associated schizophrenia and inflammation. Importantly, different lines of evidence have shown dopamine as a major regulator of inflammation. In this regard, dopamine might exert strong regulation in the activity, migration, differentiation, and proliferation of immune cells that have been shown to contribute to cognitive functions, including T-cells, microglial cells, and peripheral monocytes. Thereby, alterations in dopamine levels associated to schizophrenia might affect inflammatory response of immune cells and consequently some behavioral functions, including reference memory, learning, social behavior, and stress resilience. Altogether these findings support the involvement of an active cross-talk between the dopaminergic and immune systems in the physiopathology of schizophrenia. In this review we summarize, integrate, and discuss the current evidence indicating the involvement of an altered dopaminergic regulation of immunity in schizophrenia.
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Affiliation(s)
- Pia M Vidal
- Department of Basic Science, Biomedical Science Research Lab, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción, Chile.,Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, Santiago, Chile
| | - Rodrigo Pacheco
- Laboratorio de Neuroinmunología, Fundación Ciencia & Vida, Santiago, Chile.,Universidad San Sebastián, Santiago, Chile
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10
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Zhou X, Wang X, Li R, Yan J, Xiao Y, Li W, Shen H. Neutrophil-to-Lymphocyte Ratio Is Independently Associated With Severe Psychopathology in Schizophrenia and Is Changed by Antipsychotic Administration: A Large-Scale Cross-Sectional Retrospective Study. Front Psychiatry 2020; 11:581061. [PMID: 33192726 PMCID: PMC7661461 DOI: 10.3389/fpsyt.2020.581061] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/18/2020] [Indexed: 12/21/2022] Open
Abstract
Background: Immunological and inflammatory mechanisms play an important role in schizophrenia. The neutrophil-to-lymphocyte ratio (NLR) is a value obtained by dividing the absolute number of neutrophils by the absolute lymphocyte count and represents a biomarker of systemic inflammatory response. There are studies investigating NLR association with psychopathology. However, the relationship has been only studied in small numbers of patients with schizophrenia, which leads to conflicting results and makes the meta-analytic data difficult to interpret. The aim of this study is to perform large-scale cross-sectional analysis on the potential correlation between NLR and disease severity in schizophrenic patients with or without medication. Methods: This cross-sectional retrospective study was conducted in Nanjing Medical University Affiliated Brain Hospital. We identified inpatients with schizophrenia between July 12, 2018 and March 27, 2019 and collected data of NLR, the Clinical Global Impression Severity scale (CGI-S) score and the Brief Psychiatric Rating Scale (BPRS) score. Results: The records of 1,144 identified patients (10.8% drug-free patients) were analyzed. We found that NLR was significantly decreased in schizophrenic patients after antipsychotic administration and there was the discrepant correlation between NLR and psychiatric symptoms in patients with or without antipsychotic medication. The results of multivariate logistic regressions showed that NLR was positively associated with the severity of disease (i.e., the CGI-S score and the BPRS total score) in drug-free patients, and it was negatively associated with the BPRS negative symptoms (i.e., the BPRS negative symptoms score) in drug-therapy patients. Conclusion: The study is the first to confirm the hypothesis that NLR is independently associated with severe psychopathology in schizophrenia and is changed by antipsychotic administration.
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Affiliation(s)
- Xia Zhou
- Neuro-Psychiatric Institute, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
| | - Xiaolan Wang
- Department of Psychiatry, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
| | - Rui Li
- School of Pharmacy, Nanjing Medical University, Nanjing, China
| | - Jun Yan
- Department of Geriatric Neurology, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
| | - Ying Xiao
- College of Science, China Pharmaceutical University, Nanjing, China
| | - Weiguang Li
- College of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Hong Shen
- Neuro-Psychiatric Institute, Nanjing Medical University Affiliated Brain Hospital, Nanjing, China
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11
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Meygooni MS, Asil MAM, Haftvani GT, Morshedzadeh F, Zaeifi D. Auxiliary role of D5 dopamine receptor as a marker in paranoid schizophrenia patients. PSYCHIAT CLIN PSYCH 2019. [DOI: 10.1080/24750573.2019.1575501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Affiliation(s)
| | | | | | - Firouzeh Morshedzadeh
- Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Davood Zaeifi
- Department of Biology, North-Tehran branch, Islamic Azad University, Tehran, Iran
- Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
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12
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The key role of T cells in Parkinson's disease pathogenesis and therapy. Parkinsonism Relat Disord 2018; 60:25-31. [PMID: 30404763 DOI: 10.1016/j.parkreldis.2018.10.029] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 09/20/2018] [Accepted: 10/26/2018] [Indexed: 12/20/2022]
Abstract
This review focuses on the role of T lymphocytes in the pathogenesis of Parkinson's disease and highlights evidence for modulation of the T cell response as an effective neuroprotective strategy. In preclinical models of Parkinson's disease, modulation of the T cell response results in neuroprotection. Peripheral markers of T cell response show changes in Parkinson's patients relative to controls that have potential application as diagnostic and therapeutic biomarkers. The article also discusses the important immunomodulatory effects of dopamine which may confound study of T cells in patients on dopaminergic therapies, and highlights glatiramer acetate, an FDA-approved therapy for multiple sclerosis that works through modulating the T cell response, as a promising target for translation.
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13
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Sadat-Shirazi MS, Vousooghi N, Alizadeh B, Makki SM, Zarei SZ, Nazari S, Zarrindast MR. Expression of NMDA receptor subunits in human blood lymphocytes: A peripheral biomarker in online computer game addiction. J Behav Addict 2018; 7:260-268. [PMID: 29788757 PMCID: PMC6174581 DOI: 10.1556/2006.7.2018.35] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background and aims Repeated performance of some behaviors such as playing computer games could result in addiction. The NMDA receptor is critically involved in the development of behavioral and drug addictions. It has been claimed that the expression level of neurotransmitter receptors in the brain may be reflected in peripheral blood lymphocytes (PBLs). Methods Here, using a real-time PCR method, we have investigated the mRNA expression of GluN2A, GluN2D, GluN3A, and GluN3B subunits of the NMDA receptor in PBLs of male online computer game addicts (n = 25) in comparison with normal subjects (n = 26). Results Expression levels of GluN2A, GluN2D, and GluN3B subunits were not statistically different between game addicts and the control group. However, the mRNA expression of the GluN3A subunit was downregulated in PBLs of game addicts. Discussion and conclusions Transcriptional levels of GluN2A and GluN2D subunits in online computer game addicts are similar to our previously reported data of opioid addiction and are not different from the control group. However, unlike our earlier finding of drug addiction, the mRNA expression levels of GluN3A and GluN3B subunits in PBLs of game addicts are reduced and unchanged, respectively, compared with control subjects. It seems that the downregulated state of the GluN3A subunit of NMDA receptor in online computer game addicts is a finding that deserves more studies in the future to see whether it can serve as a peripheral biomarker in addiction studies, where the researcher wants to rule out the confusing effects of abused drugs.
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Affiliation(s)
- Mitra-Sadat Sadat-Shirazi
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran,Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Vousooghi
- Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran,Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran,Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran,Corresponding author: Nasim Vousooghi, Pharm D, PhD; Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, PO Box 1417755469, Tehran, Iran; Phone: +98 21 8899 1118; Fax: +98 21 8899 1117; E-mail:
| | - Bentolhoda Alizadeh
- Department of Biology, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Mohammad Makki
- Department of Psychiatry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shahrzad Nazari
- Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zarrindast
- Genetics Laboratory, Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran,Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran,School of Cognitive Sciences, Institute for Studies in Theoretical Physics and Mathematics, Tehran, Iran,Institute for Cognitive Science Studies, Tehran, Iran
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Talhada D, Rabenstein M, Ruscher K. The role of dopaminergic immune cell signalling in poststroke inflammation. Ther Adv Neurol Disord 2018; 11:1756286418774225. [PMID: 29774058 PMCID: PMC5952273 DOI: 10.1177/1756286418774225] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 04/06/2018] [Indexed: 01/08/2023] Open
Abstract
Upon ischaemic stroke, brain-resident and peripheral immune cells accumulate in the central nervous system (CNS). Interestingly, these cells express pattern specific to neurotransmitter receptors and, therefore, seem to be susceptible to neurotransmitter stimulation, potentially modulating their properties and functions. One of the principal neurotransmitters in the CNS, dopamine, is involved in the regulation of processes of brain development, motor control and higher brain functions. It is constantly released in the brain and there is experimental and clinical evidence that dopaminergic signalling is involved in recovery of lost neurological function after stroke. Independent studies have revealed specific but different patterns of dopamine receptor subtypes on different populations of immune cells. Those patterns are dependent on the activation status of cells. Generally, exposure to dopamine or dopamine receptor agonists decreases detrimental actions of immune cells. In contrast, a reduction of dopaminergic inputs perpetuates a pro-inflammatory state associated with increased release of pro-inflammatory molecules. In addition, subsets of immune cells have been identified to synthesize and release dopamine, suggesting autoregulatory mechanisms. Evidence supports that inflammatory processes activated following ischaemic stroke are modulated by dopaminergic signalling.
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Affiliation(s)
- Daniela Talhada
- LUBIN Lab – Lund Brain Injury Laboratory for Neurosurgical Research, Department of Clinical Sciences, Lund University, Lund, Sweden CICS-UBI-Health Sciences Research Centre, Faculdade de Ciências da Saúde, Av. Infante D. Henrique, Universidade da Beira Interior, Portugal
| | - Monika Rabenstein
- Department of Neurology, University Hospital Cologne, Cologne, Germany
| | - Karsten Ruscher
- Lund Brain Injury Laboratory for Neurosurgical Research, Wallenberg Neuroscience Center, Lund University, BMC A13, S-22184 Lund, Sweden
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Taraskina AE, Nasyrova RF, Zabotina AM, Sosin DN, Sosina КА, Ershov EE, Grunina MN, Krupitsky EM. Potential diagnostic markers of olanzapine efficiency for acute psychosis: a focus on peripheral biogenic amines. BMC Psychiatry 2017; 17:394. [PMID: 29221470 PMCID: PMC5723030 DOI: 10.1186/s12888-017-1562-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 11/30/2017] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Biomarkers are now widely used in many fields of medicine, and the identification of biomarkers that predict antipsychotic efficacy and adverse reactions is a growing area of psychiatric research. Monoamine molecules of the peripheral bloodstream are possible prospective biomarkers based on a growing body of evidence indicating that they may reflect specific changes in neurotransmitters in the brain. The aim of this study was to detect peripheral biogenic amine indicators of patients with acute psychosis and to test the correlations between the biological measures studied and the psychopathological status of the patients. METHODS This research included 60 patients with acute psychosis treated with olanzapine (n = 30) or haloperidol (n = 30). Here, we measured biogenic amine indicators, including mRNA levels of dopamine receptor D4 (DRD4) and the serotonin 2A receptor (5HTR2A), in peripheral blood mononuclear cells (PBMCs) using quantitative real-time polymerase chain reaction and serum dopamine concentrations by enzyme linked immunosorbent assay (ELISA). Psychopathological status was evaluated using psychometric scales. The assessments were conducted prior to and after 14 and 28 days of treatment. RESULTS The administration of haloperidol, but not olanzapine, up-regulated 5HTR2A mRNA in a linear manner, albeit without statistical significance (p = 0.052). Both drugs had non-significant effects on DRD4 mRNA levels. Nevertheless, a positive correlation was found between DRD4 and 5HTR2A mRNA levels over a longitudinal trajectory, suggesting co-expression of the two genes. A significant positive correlation was observed between 5HTR2A mRNA levels and total Positive and Negative Syndrome Scale (PANSS) scores in both groups of patients before treatment. A significant correlation between baseline 5HTR2A mRNA levels and PANSS scores on days 14 and 28 of treatment remained for patients treated with olanzapine only. Moreover, a significant positive correlation was observed between blood serum dopamine levels and scores on extrapyramidal symptom scales in the olanzapine group. CONCLUSIONS The DRD4 and 5HTR2A genes are co-expressed in PBMCs during antipsychotic administration. Despite a correlation between the studied biogenic amine indicators and the psychopathological status of patients, reliable biomarkers of treatment response could not be determined.
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Affiliation(s)
- A. E. Taraskina
- Department of Addictions, Department of personalized psychiatry and neurology, V.M. Bekhterev National Medical Research Center Psychiatry and Neurology, ul. Bekhterev, d. 3, Saint-Petersburg, 192019 Russia
- Laboratory of Molecular Biology, First Saint Petersburg Pavlov State Medical University, L’va Tolstogo str. 6/8, Saint-Petersburg, 197022 Russia
- Laboratory of Molecular Human Genetics, National Research Centre “Kurchatov Institute”, Petersburg Nuclear Physics Institute named after B.P. Konstantinov, Leningrad district, Orlova Roscha, Leningrad district, Gatchina, 188300 Russia
| | - R. F. Nasyrova
- Department of Addictions, Department of personalized psychiatry and neurology, V.M. Bekhterev National Medical Research Center Psychiatry and Neurology, ul. Bekhterev, d. 3, Saint-Petersburg, 192019 Russia
| | - A. M. Zabotina
- Laboratory of Molecular Biology, First Saint Petersburg Pavlov State Medical University, L’va Tolstogo str. 6/8, Saint-Petersburg, 197022 Russia
- Laboratory of Molecular Human Genetics, National Research Centre “Kurchatov Institute”, Petersburg Nuclear Physics Institute named after B.P. Konstantinov, Leningrad district, Orlova Roscha, Leningrad district, Gatchina, 188300 Russia
| | - D. N. Sosin
- Department of Addictions, Department of personalized psychiatry and neurology, V.M. Bekhterev National Medical Research Center Psychiatry and Neurology, ul. Bekhterev, d. 3, Saint-Petersburg, 192019 Russia
| | - К. А. Sosina
- Department of Addictions, Department of personalized psychiatry and neurology, V.M. Bekhterev National Medical Research Center Psychiatry and Neurology, ul. Bekhterev, d. 3, Saint-Petersburg, 192019 Russia
| | - E. E. Ershov
- Saint Petersburg Psychiatric Hospital no. 1 named after P.P. Kashchenko, Leningrad region, district, s. Nikolskoye, ul. Menkovskaya, d. 10, Gatchina, Russia
| | - M. N. Grunina
- Laboratory of Molecular Human Genetics, National Research Centre “Kurchatov Institute”, Petersburg Nuclear Physics Institute named after B.P. Konstantinov, Leningrad district, Orlova Roscha, Leningrad district, Gatchina, 188300 Russia
| | - E. M. Krupitsky
- Department of Addictions, Department of personalized psychiatry and neurology, V.M. Bekhterev National Medical Research Center Psychiatry and Neurology, ul. Bekhterev, d. 3, Saint-Petersburg, 192019 Russia
- Laboratory of Molecular Biology, First Saint Petersburg Pavlov State Medical University, L’va Tolstogo str. 6/8, Saint-Petersburg, 197022 Russia
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Perkovic MN, Erjavec GN, Strac DS, Uzun S, Kozumplik O, Pivac N. Theranostic Biomarkers for Schizophrenia. Int J Mol Sci 2017; 18:E733. [PMID: 28358316 PMCID: PMC5412319 DOI: 10.3390/ijms18040733] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 03/23/2017] [Accepted: 03/27/2017] [Indexed: 12/14/2022] Open
Abstract
Schizophrenia is a highly heritable, chronic, severe, disabling neurodevelopmental brain disorder with a heterogeneous genetic and neurobiological background, which is still poorly understood. To allow better diagnostic procedures and therapeutic strategies in schizophrenia patients, use of easy accessible biomarkers is suggested. The most frequently used biomarkers in schizophrenia are those associated with the neuroimmune and neuroendocrine system, metabolism, different neurotransmitter systems and neurotrophic factors. However, there are still no validated and reliable biomarkers in clinical use for schizophrenia. This review will address potential biomarkers in schizophrenia. It will discuss biomarkers in schizophrenia and propose the use of specific blood-based panels that will include a set of markers associated with immune processes, metabolic disorders, and neuroendocrine/neurotrophin/neurotransmitter alterations. The combination of different markers, or complex multi-marker panels, might help in the discrimination of patients with different underlying pathologies and in the better classification of the more homogenous groups. Therefore, the development of the diagnostic, prognostic and theranostic biomarkers is an urgent and an unmet need in psychiatry, with the aim of improving diagnosis, therapy monitoring, prediction of treatment outcome and focus on the personal medicine approach in order to improve the quality of life in patients with schizophrenia and decrease health costs worldwide.
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Affiliation(s)
| | | | - Dubravka Svob Strac
- Rudjer Boskovic Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia.
| | - Suzana Uzun
- Clinic for Psychiatry Vrapce, 10090 Zagreb, Croatia.
| | | | - Nela Pivac
- Rudjer Boskovic Institute, Division of Molecular Medicine, 10000 Zagreb, Croatia.
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Levite M, Marino F, Cosentino M. Dopamine, T cells and multiple sclerosis (MS). J Neural Transm (Vienna) 2017; 124:525-542. [DOI: 10.1007/s00702-016-1640-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 10/31/2016] [Indexed: 01/11/2023]
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18
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Immunomodulatory Effects Mediated by Dopamine. J Immunol Res 2016; 2016:3160486. [PMID: 27795960 PMCID: PMC5067323 DOI: 10.1155/2016/3160486] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 07/29/2016] [Accepted: 08/08/2016] [Indexed: 01/11/2023] Open
Abstract
Dopamine (DA), a neurotransmitter in the central nervous system (CNS), has modulatory functions at the systemic level. The peripheral and central nervous systems have independent dopaminergic system (DAS) that share mechanisms and molecular machinery. In the past century, experimental evidence has accumulated on the proteins knowledge that is involved in the synthesis, reuptake, and transportation of DA in leukocytes and the differential expression of the D1-like (D1R and D5R) and D2-like receptors (D2R, D3R, and D4R). The expression of these components depends on the state of cellular activation and the concentration and time of exposure to DA. Receptors that are expressed in leukocytes are linked to signaling pathways that are mediated by changes in cAMP concentration, which in turn triggers changes in phenotype and cellular function. According to the leukocyte lineage, the effects of DA are associated with such processes as respiratory burst, cytokine and antibody secretion, chemotaxis, apoptosis, and cytotoxicity. In clinical conditions such as schizophrenia, Parkinson disease, Tourette syndrome, and multiple sclerosis (MS), there are evident alterations during immune responses in leukocytes, in which changes in DA receptor density have been observed. Several groups have proposed that these findings are useful in establishing clinical status and clinical markers.
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Fernandez-Egea E, Vértes PE, Flint SM, Turner L, Mustafa S, Hatton A, Smith KGC, Lyons PA, Bullmore ET. Peripheral Immune Cell Populations Associated with Cognitive Deficits and Negative Symptoms of Treatment-Resistant Schizophrenia. PLoS One 2016; 11:e0155631. [PMID: 27244229 PMCID: PMC4887013 DOI: 10.1371/journal.pone.0155631] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Accepted: 05/01/2016] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Hypothetically, psychotic disorders could be caused or conditioned by immunological mechanisms. If so, one might expect there to be peripheral immune system phenotypes that are measurable in blood cells as biomarkers of psychotic states. METHODS We used multi-parameter flow cytometry of venous blood to quantify and determine the activation state of 73 immune cell subsets for 18 patients with chronic schizophrenia (17 treated with clozapine), and 18 healthy volunteers matched for age, sex, BMI and smoking. We used multivariate methods (partial least squares) to reduce dimensionality and define populations of differentially co-expressed cell counts in the cases compared to controls. RESULTS Schizophrenia cases had increased relative numbers of NK cells, naïve B cells, CXCR5+ memory T cells and classical monocytes; and decreased numbers of dendritic cells (DC), HLA-DR+ regulatory T-cells (Tregs), and CD4+ memory T cells. Likewise, within the patient group, more severe negative and cognitive symptoms were associated with decreased relative numbers of dendritic cells, HLA-DR+ Tregs, and CD4+ memory T cells. Motivated by the importance of central nervous system dopamine signalling for psychosis, we measured dopamine receptor gene expression in separated CD4+ cells. Expression of the dopamine D3 (DRD3) receptor was significantly increased in clozapine-treated schizophrenia and covaried significantly with differentiated T cell classes in the CD4+ lineage. CONCLUSIONS Peripheral immune cell populations and dopaminergic signalling are disrupted in clozapine-treated schizophrenia. Immuno-phenotypes may provide peripherally accessible and mechanistically specific biomarkers of residual cognitive and negative symptoms in this treatment-resistant subgroup of patients.
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Affiliation(s)
- Emilio Fernandez-Egea
- NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom
- University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom
- Centro de Investigación Biomedica en Red de Salud Mental (CIBERSAM), G04, Barcelona, Spain
- Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, United Kingdom
| | - Petra E. Vértes
- University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom
| | - Shaun M. Flint
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom
| | - Lorinda Turner
- NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom
| | - Syed Mustafa
- University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom
| | - Alex Hatton
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom
| | - Kenneth G. C. Smith
- NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom
| | - Paul A. Lyons
- Department of Medicine and Cambridge Institute for Medical Research, University of Cambridge, School of Clinical Medicine, Cambridge, United Kingdom
| | - Edward T. Bullmore
- NIHR Cambridge Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, Cambridge, United Kingdom
- University of Cambridge, Behavioural & Clinical Neuroscience Institute, Department of Psychiatry, Cambridge, United Kingdom
- Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, United Kingdom
- GlaxoSmithKline, ImmunoPsychiatry, Alternative Discovery & Development, Pharmaceutical R&D, Cambridge, United Kingdom
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Lai CY, Scarr E, Udawela M, Everall I, Chen WJ, Dean B. Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics. World J Psychiatry 2016; 6:102-17. [PMID: 27014601 PMCID: PMC4804259 DOI: 10.5498/wjp.v6.i1.102] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/20/2015] [Accepted: 12/17/2015] [Indexed: 02/05/2023] Open
Abstract
Identifying biomarkers that can be used as diagnostics or predictors of treatment response (theranostics) in people with schizophrenia (Sz) will be an important step towards being able to provide personalized treatment. Findings from the studies in brain tissue have not yet been translated into biomarkers that are practical in clinical use because brain biopsies are not acceptable and neuroimaging techniques are expensive and the results are inconclusive. Thus, in recent years, there has been search for blood-based biomarkers for Sz as a valid alternative. Although there are some encouraging preliminary data to support the notion of peripheral biomarkers for Sz, it must be acknowledged that Sz is a complex and heterogeneous disorder which needs to be further dissected into subtype using biological based and clinical markers. The scope of this review is to critically examine published blood-based biomarker of Sz, focusing on possible uses for diagnosis, treatment response, or their relationship with schizophrenia-associated phenotype. We sorted the studies into six categories which include: (1) brain-derived neurotrophic factor; (2) inflammation and immune function; (3) neurochemistry; (4) oxidative stress response and metabolism; (5) epigenetics and microRNA; and (6) transcriptome and proteome studies. This review also summarized the molecules which have been conclusively reported as potential blood-based biomarkers for Sz in different blood cell types. Finally, we further discusses the pitfall of current blood-based studies and suggest that a prediction model-based, Sz specific, blood oriented study design as well as standardize blood collection conditions would be useful for Sz biomarker development.
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Levite M. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases. Acta Physiol (Oxf) 2016; 216:42-89. [PMID: 25728499 DOI: 10.1111/apha.12476] [Citation(s) in RCA: 156] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Revised: 10/07/2014] [Accepted: 02/23/2015] [Indexed: 12/12/2022]
Abstract
Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >>>CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, Fyn, NF-κB, KLF2), (x) T cells produce dopamine (Tregs>>>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen-specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, Schizophrenia and Tourette), patient's T cells seem to have abnormal DRs expression and/or responses to dopamine or production of dopamine, (xiii) drugs that affect the dopaminergic system have potent effects on T cells (e.g. dopamine=Intropin, L-dopa, bromocriptine, haloperidol, quinpirole, reserpine, pergolide, ecopipam, pimozide, amantadine, tetrabenazine, nomifensine, butaclamol). Dopamine-induced activation of resting Teffs and suppression of Tregs seem beneficial for health and may also be used for immunotherapy of cancer and infectious diseases. Independently, suppression of DRs in autoimmune and pro-inflammatory T cells, and also in cancerous T cells, may be advantageous. The review is relevant to Immunologists, Neurologists, Neuroimmunologists, Hematologists, Psychiatrists, Psychologists and Pharmacologists.
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Affiliation(s)
- M. Levite
- School of Pharmacy; Faculty of Medicine; The Hebrew University; Jerusalem Israel
- Institute of Gene Therapy; Hadassah Hebrew University Hospital; Jerusalem Israel
- School of Behavioral Sciences; Academic College of Tel-Aviv-Yaffo; Tel Aviv Israel
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Akbari ME, Kashani FL, Ahangari G, Pornour M, Hejazi H, Nooshinfar E, Kabiri M, Hosseini L. The effects of spiritual intervention and changes in dopamine receptor gene expression in breast cancer patients. Breast Cancer 2015; 23:893-900. [PMID: 26597879 DOI: 10.1007/s12282-015-0658-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 10/30/2015] [Indexed: 01/11/2023]
Abstract
Breast cancer is the most common cancer in females in Iran and in most of the developed countries. Studies have shown that having chronic stress in individuals predisposes several types of cancer including breast cancer. Research results showed that spiritual factors correlate with indices of physical consequences such as heart disease, cancer, and death, so do psychiatric conditions and changes in receptor gene expression in depression, anxiety, and social dysfunction. Different studies demonstrated the role of neurotransmitters in occurrence and progression of cancers. They affected cells by their various types of receptors. An effective gene in mental and physical conditions is Dopamine receptor. Accordingly, the study was conducted to evaluate effects of psychotherapy (spiritual intervention) on changes in Dopamine receptor gene expressions in breast cancer patients. 90 female volunteers, including 30 healthy individuals and 60 diagnosed with breast cancer, considering exclusion criteria, were selected for the purpose of the study. The breast cancer patients were further categorized into experimental and control groups of 30 each. Blood samples were collected both prior to and following the spiritual intervention to analyze changes in their dopamine gene receptor expressions. We observed that DRD2-DRD4 in the control group (breast cancer patients) PBMC increased compared to healthy individuals. Also, DRD2-DRD4 in intervention group PBMC decreased compared to the control group and to even lower than those of healthy individuals. The findings were of great significance in management and treatment of cancer because they revealed the possibility of using alternative treatments (e.g., spiritual interventions) apart from conventional medical treatments.
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Affiliation(s)
- Mohammad Esmael Akbari
- Department of Surgical Oncology, Shahid Beheshti University of Medical Sciences (SBUMS), Cancer Research Center (CRC), Tehran, Iran
| | - Farah Lotfi Kashani
- Department of Psycho-oncology, Shahid Beheshti University of Medical Sciences (SBUMS), Cancer Research Center (CRC), Tehran, Iran
| | | | | | - Hessam Hejazi
- Department of Biology, Faculty of Science, Lorestan University, Khoramabad, Iran
| | - Elah Nooshinfar
- Department of Psycho-oncology, Shahid Beheshti University of Medical Sciences (SBUMS), Cancer Research Center (CRC), Tehran, Iran
| | - Mohsen Kabiri
- Department of Language, Aryanpour Institute, Tehran, Iran
| | - Leili Hosseini
- Department of Psycho-oncology, Shahid Beheshti University of Medical Sciences (SBUMS), Cancer Research Center (CRC), Tehran, Iran.
- Cancer Research Center, Shohada Hospital, Tajrish, Tehran, Iran.
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Cui Y, Prabhu V, Nguyen TB, Yadav BK, Chung YC. The mRNA Expression Status of Dopamine Receptor D2, Dopamine Receptor D3 and DARPP-32 in T Lymphocytes of Patients with Early Psychosis. Int J Mol Sci 2015; 16:26677-86. [PMID: 26561806 PMCID: PMC4661842 DOI: 10.3390/ijms161125983] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Revised: 10/22/2015] [Accepted: 10/23/2015] [Indexed: 01/22/2023] Open
Abstract
Peripheral blood lymphocytes are an attractive tool because there is accumulating evidence indicating that lymphocytes may be utilized as a biomarker in the field of psychiatric study as they could reveal the condition of cells distributed in the brain. Here, we measured the mRNA expression status of dopamine receptor D2 (DRD2), DRD3, and dopamine and cyclic adenosine 3',5'-monophosphate regulated phosphoprotein-32 (DARPP-32) in T lymphocytes of patients with early psychosis by quantitative real-time polymerase chain reaction (q-PCR) and explored the relationships between their mRNA levels and the psychopathological status of patients. The present study demonstrated that the mRNA expression levels of DRD3 in T lymphocytes were significantly different among controls, and in patients with psychotic disorder not otherwise specified (NOS) and schizophrenia/schizophreniform disorder. However, no significant differences in mRNA expression levels of DRD2 and DARPP-32 were found among the three groups. We found a significant positive correlation between the DRD2 mRNA level and the score of the excited factor of the Positive and Negative Syndrome Scale (PANSS) in patients with schizophrenia/schizophreniform disorder. These findings suggest that DRD3 mRNA levels may serve as a potential diagnostic biomarker differentiating patients with early psychosis from controls.
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Affiliation(s)
- Yin Cui
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Vishwanath Prabhu
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Thong Ba Nguyen
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Binod Kumar Yadav
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
| | - Young-Chul Chung
- Department of Psychiatry, Chonbuk National University Medical School, Jeonju 561-756, Korea.
- Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju 561-756, Korea.
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Adaptive Immunity in Schizophrenia: Functional Implications of T Cells in the Etiology, Course and Treatment. J Neuroimmune Pharmacol 2015; 10:610-9. [PMID: 26162591 DOI: 10.1007/s11481-015-9626-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 07/03/2015] [Indexed: 12/21/2022]
Abstract
Schizophrenia is a severe and highly complex neurodevelopmental disorder with an unknown etiopathology. Recently, immunopathogenesis has emerged as one of the most compelling etiological models of schizophrenia. Over the past few years considerable research has been devoted to the role of innate immune responses in schizophrenia. The findings of such studies have helped to conceptualize schizophrenia as a chronic low-grade inflammatory disorder. Although the contribution of adaptive immune responses has also been emphasized, however, the precise role of T cells in the underlying neurobiological pathways of schizophrenia is yet to be ascertained comprehensively. T cells have the ability to infiltrate brain and mediate neuro-immune cross-talk. Conversely, the central nervous system and the neurotransmitters are capable of regulating the immune system. Neurotransmitter like dopamine, implicated widely in schizophrenia risk and progression can modulate the proliferation, trafficking and functions of T cells. Within brain, T cells activate microglia, induce production of pro-inflammatory cytokines as well as reactive oxygen species and subsequently lead to neuroinflammation. Importantly, such processes contribute to neuronal injury/death and are gradually being implicated as mediators of neuroprogressive changes in schizophrenia. Antipsychotic drugs, commonly used to treat schizophrenia are also known to affect adaptive immune system; interfere with the differentiation and functions of T cells. This understanding suggests a pivotal role of T cells in the etiology, course and treatment of schizophrenia and forms the basis of this review.
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Vousooghi N, Zarei SZ, Sadat-Shirazi MS, Eghbali F, Zarrindast MR. mRNA expression of dopamine receptors in peripheral blood lymphocytes of computer game addicts. J Neural Transm (Vienna) 2015; 122:1391-8. [DOI: 10.1007/s00702-015-1408-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 05/04/2015] [Indexed: 12/24/2022]
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Santoro ML, Ota VK, Stilhano RS, Silva PN, Santos CM, Diana MC, Gadelha A, Bressan RA, Melaragno MI, Han SW, Abílio VC, Belangero SI. Effect of antipsychotic drugs on gene expression in the prefrontal cortex and nucleus accumbens in the spontaneously hypertensive rat (SHR). Schizophr Res 2014; 157:163-8. [PMID: 24893910 DOI: 10.1016/j.schres.2014.05.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 04/03/2014] [Accepted: 05/05/2014] [Indexed: 12/19/2022]
Abstract
Antipsychotic drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was Drd2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied.
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Affiliation(s)
- Marcos Leite Santoro
- Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitao da Cunha, 1° andar, CEP 04023-900 São Paulo, Brazil; LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil
| | - Vanessa Kiyomi Ota
- Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitao da Cunha, 1° andar, CEP 04023-900 São Paulo, Brazil; LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil
| | - Roberta Sessa Stilhano
- Department of Biophysics and Investigation Center for Gene Therapy, Universidade Federal de Sao Paulo (UNIFESP), Rua Mirassol 207, CEP:04044-010, Brazil
| | - Patrícia Natália Silva
- Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitao da Cunha, 1° andar, CEP 04023-900 São Paulo, Brazil; LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil
| | - Camila Maurício Santos
- LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil; Department of Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Rua Pedro de Toledo 669, 5th floor, CEP: 04039032, Brazil
| | - Mariana Cepollaro Diana
- LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil; Department of Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Rua Pedro de Toledo 669, 5th floor, CEP: 04039032, Brazil
| | - Ary Gadelha
- LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil
| | - Rodrigo Affonseca Bressan
- LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil
| | - Maria Isabel Melaragno
- Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitao da Cunha, 1° andar, CEP 04023-900 São Paulo, Brazil
| | - Sang Won Han
- Department of Biophysics and Investigation Center for Gene Therapy, Universidade Federal de Sao Paulo (UNIFESP), Rua Mirassol 207, CEP:04044-010, Brazil
| | - Vanessa Costhek Abílio
- LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil; Department of Pharmacology, Universidade Federal de Sao Paulo (UNIFESP), Rua Pedro de Toledo 669, 5th floor, CEP: 04039032, Brazil
| | - Sintia Iole Belangero
- Genetics Division, Department of Morphology and Genetics, Universidade Federal de Sao Paulo (UNIFESP), Rua Botucatu, 740, Edifício Leitao da Cunha, 1° andar, CEP 04023-900 São Paulo, Brazil; LiNC - Interdisciplinary Lab of Clinical Neurosciences, Department of Psychiatry, UNIFESP, Rua Pedro de Toledo, 669, 3° floor, CEP 05039-032 São Paulo, Brazil.
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Analysis of association between dopamine receptor genes’ methylation and their expression profile with the risk of schizophrenia. Psychiatr Genet 2013; 23:183-7. [DOI: 10.1097/ypg.0b013e328363d6e1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Buttarelli FR, Fanciulli A, Pellicano C, Pontieri FE. The dopaminergic system in peripheral blood lymphocytes: from physiology to pharmacology and potential applications to neuropsychiatric disorders. Curr Neuropharmacol 2012; 9:278-88. [PMID: 22131937 PMCID: PMC3131719 DOI: 10.2174/157015911795596612] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2010] [Revised: 09/17/2010] [Accepted: 09/24/2010] [Indexed: 12/12/2022] Open
Abstract
Besides its action on the nervous system, dopamine (DA) plays a role on neural-immune interactions. Here we review the current evidence on the dopaminergic system in human peripheral blood lymphocytes (PBL). PBL synthesize DA through the tyrosine-hydroxylase/DOPA-decarboxylase pathway, and express DA receptors and DA transporter (DAT) on their plasma membrane. Stimulation of DA receptors on PBL membrane contributes to modulate the development and initiation of immune responses under physiological conditions and in immune system pathologies such as autoimmunity or immunodeficiency. The characterization of DA system in PBL gave rise to a further line of research investigating the feasibility of PBL as a cellular model for studying DA derangement in neuropsychiatric disorders. Several reports showed changes of the expression of DAT and/or DA receptors in PBL from patients suffering from several neuropsychiatric disorders, in particular parkinsonian syndromes, schizophrenia and drug- or alcohol-abuse. Despite some methodological and theoretical limitations, these findings suggest that PBL may prove a cellular tool with which to identify the derangement of DA transmission in neuropsychiatric diseases, as well as to monitor the effects of pharmacological treatments.
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Increase in dopaminergic, but not serotoninergic, receptors in T-cells as a marker for schizophrenia severity. J Psychiatr Res 2012; 46:738-42. [PMID: 22497994 DOI: 10.1016/j.jpsychires.2012.03.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Revised: 02/10/2012] [Accepted: 03/02/2012] [Indexed: 11/22/2022]
Abstract
Schizophrenia is characterized by a slow deteriorating mental illness. Although the pathophysiology mechanisms are not fully understood, different studies have suggested a role for the immune system in the pathogenesis of schizophrenia. To date, an altered expression or signaling of neurotransmitters receptors is observed in immune cells during psychiatric disorders. In the present study, we investigated the expression of different serotonin and dopamine receptors in T-cells of schizophrenic and control patients. We used flow cytometry to determine the pattern of expression of dopamine (D2 and D4) and serotonine receptors (SR1A, SR1C, SR2A, SR2B), as well as serotonin transporter (ST), in T-cell subsets (CD4 and CD8). Expression of serotonin receptors and ST in T-cells of schizophrenic patients were not different from controls. However, the percentages of CD4+D4+ and CD8+D4+ were increased in schizophrenic patients as compared to controls. In addition, increased percentages of CD8+D2+ cells were also observed in schizophrenic patients, albeit this population revealed lower CD4+D2+ cells in comparison to controls. Interestingly, a relationship between clinical symptoms and immunological parameters was also observed. We showed that the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were positively related to CD8+D2+ cells, though AIMS was inversely related to CD4+D4+ cells. In conclusion, the alteration in the pattern of cell population and molecules expressed by them might serve as a promising biomarker for diagnosis of schizophrenia.
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Abstract
Molecular biomarkers for antipsychotic treatments have been conceptually linked to the measurements of dopamine functions, mostly D(2) receptor occupancy, either by imaging using selective PET/SPECT radioactive tracers or by assessing plasma prolactin levels. A quest for novel biomarkers was recently proposed by various academic, health service, and industrial institutions driven by the need for better treatments of psychoses. In this review we conceptualize biomarkers within the Translational Medicine paradigm whose goal was to provide support to critical decision-making in drug discovery. At first we focused on biomarkers as outcome measure of clinical studies by searching into the database clinicaltrial.gov. The results were somewhat disappointing, showing that out of 1,659 antipsychotic trials only 18 used a biomarker as an outcome measure. Several of these trials targeted plasma lipids as sentinel marker for metabolic adverse effects associated with the use of atypical antipsychotics, while only few studies were aimed to new disease specific biological markers. As an example of a mechanistic biomarker, we described the work done to progress the novel class of glycine transporter inhibitors as putative treatment for negative symptoms of schizophrenia. We also review how large-scale multiplex biological assays were applied to samples from tissues of psychiatric patients, so to learn from changes of numerous analytes (metabolic products, lipids, proteins, RNA transcripts) about the substrates involved in the disease. We concluded that a stringent implementation of these techniques could contribute to the endophenotypic characterization of patients, helping in the identification of key biomarkers to drive personalized medicine and new treatment development.
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Affiliation(s)
- Emilio Merlo Pich
- Respiratory Therapeutic Area, GlaxoSmithKline R&D, King of Prussia, PA, USA.
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Taurines R, Grünblatt E, Schecklmann M, Schwenck C, Albantakis L, Reefschläger L, Walitza S, Renner T, Gerlach M, Thome J, Romanos M. Altered mRNA expression of monoaminergic candidate genes in the blood of children with attention deficit hyperactivity disorder and autism spectrum disorder. World J Biol Psychiatry 2011; 12 Suppl 1:104-8. [PMID: 21906006 DOI: 10.3109/15622975.2011.600297] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES In absence of objective clinical characteristics the identification of peripheral biomarkers in neuropsychiatric disorders is highly relevant for the diagnostic process and an individualized therapy. We analyzed mRNA-expression of monoaminergic candidate genes (DRD4, DRD5, TPH1) in peripheral tissue of patients with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), highly comorbid with ADHD, searching for possible molecular markers for these disorders. METHODS mRNA was obtained from children and adolescents with ADHD (n = 51) and ASD (n = 26), diagnosed according to ICD-10 criteria, as well as healthy controls (n = 39). mRNA expression was determined via quantitative realtime PCR (qRT-PCR) from whole blood cells. RESULTS The concentrations of DRD4-mRNA in the whole blood were significantly lower in ADHD and ASD children (19 of 26 comorbid with ADHD) compared to healthy controls. ASD patients revealed a significantly decreased DRD5 mRNA expression in comparison to the two other groups. CONCLUSIONS Alterations in mRNA expression patterns provide further evidence for a relevant effect of the respective candidate genes in the pathophysiology of ADHD. Given their potential as biomarkers mRNA expression patterns may be useful tools in (differential-) diagnostic procedures of ADHD and ASD. Future studies may determine the sensitivity and specificity of these putative biomarkers in larger samples including further neuropsychiatric diagnoses.
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Affiliation(s)
- Regina Taurines
- Hospital of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.
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Rotter A, Asemann R, Decker A, Kornhuber J, Biermann T. Orexin expression and promoter-methylation in peripheral blood of patients suffering from major depressive disorder. J Affect Disord 2011; 131:186-92. [PMID: 21211849 DOI: 10.1016/j.jad.2010.12.004] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2010] [Revised: 12/01/2010] [Accepted: 12/01/2010] [Indexed: 11/16/2022]
Abstract
Orexins are endogenous neuropeptides synthesized in hypothalamic neurones; they play a major role in the regulation of feeding, drinking, endocrine function and sleep/wakefulness that is often disturbed in major depression. The aim of this study was to explore Orexin A expression and promotermethylation in peripheral blood cells of 29 patients (14 male and 15 female patients at three different time points during antidepressive treatment) suffering from major depressive disorder (MDD) by quantitative RT-PCR and bisulfite sequencing. There was a measurable difference between Orexin A expression on admission in comparison to the Orexin mRNA expression in the healthy control group (T=1.53; df=39; p=0.135) that failed to reach statistical significance. An inverse correlation between Orexin A mRNA expression on admission and the HAMD scores at all measurement dates each week over 6 weeks could be detected. A cluster of methylated CPG sites within the promoter region of the Orexin A gene could be identified that was positively correlated with Delta CT values of the mRNA expression 14 days after hospital admission (r=0.625; p=0.072) and 4 weeks afterwards (r=0.582; p=0.1). Considering only the methylation of the 7 CPGs within the CPG island in the promoter 4 weeks after treatment onset a statistically significant relation between the cluster of CPG sites within the island and body weight (r=0.55; p=0.034) as well as BMI (r=0.474; p=0.074) could be detected. Furthermore, this methylation pattern 4 weeks after treatment onset was positively associated with mRNA expression on admission, 2 and 4 weeks afterwards. In sum, these results are an indicator of a link between social stresses, disruptions in energy homeostasis and changes in body weight in relation to depressive disorders that are possibly linked to Orexin dysregulation.
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Affiliation(s)
- Andrea Rotter
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
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Nakagome K, Imamura M, Okada H, Kawahata K, Inoue T, Hashimoto K, Harada H, Higashi T, Takagi R, Nakano K, Hagiwara K, Kanazawa M, Dohi M, Nagata M, Matsushita S. Dopamine D1-like receptor antagonist attenuates Th17-mediated immune response and ovalbumin antigen-induced neutrophilic airway inflammation. THE JOURNAL OF IMMUNOLOGY 2011; 186:5975-82. [PMID: 21471450 DOI: 10.4049/jimmunol.1001274] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Allergic airway inflammation is generally considered a Th2-type immune response. Recent studies, however, demonstrated that Th17-type immune responses also play important roles in this process, especially in the pathogenesis of neutrophilic airway inflammation, a hallmark of severe asthma. We previously reported that dendritic cells release dopamine to naive CD4(+) T cells in Ag-specific cell-cell interaction, in turn inducing Th17 differentiation through dopamine D1-like receptor (D1-like-R). D1-like-R antagonist attenuates Th17-mediated diseases such as experimental autoimmune encephalomyelitis and autoimmune diabetes. However, the effect of antagonizing D1-like-R on Th17-mediated airway inflammation has yet to be studied. In this study, we examined whether D1-like-R antagonist suppresses OVA-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice and then elucidated the mechanism of action. DO11.10 mice were nebulized with OVA or PBS, and some mice received D1-like-R antagonist orally before OVA nebulization. D1-like-R antagonist significantly suppressed OVA-induced neutrophilic airway inflammation in DO11.10 mice. It also inhibited the production of IL-17 and infiltration of Th17 cells in the lung. Further, D1-like-R antagonist suppressed the production of IL-23 by lung CD11c(+) APCs. In contrast, D1-like-R antagonist did not increase Foxp3(+) regulatory T cells in the lung. D1-like-R antagonist neither suppressed nonspecific LPS-induced neutrophilic airway inflammation nor OVA-induced eosinophilic airway inflammation. These results indicate that D1-like-R antagonist could suppress Th17-mediated neutrophilic airway inflammation, raising the possibility that antagonizing D1-like-R serves as a promising new strategy for treating neutrophil-dominant severe asthma.
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Affiliation(s)
- Kazuyuki Nakagome
- Department of Respiratory Medicine, Saitama Medical University, Saitama 350-0495, Japan
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Kawano M, Sawada K, Tsuru E, Nishihara M, Kato K, Honer WG, Shimodera S. Dopamine receptor D3R and D4R mRNA levels in peripheral lymphocytes in patients with schizophrenia correlate with severity of illness. ACTA ACUST UNITED AC 2011. [DOI: 10.4236/ojpsych.2011.12006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Is the dopamine D3 receptor mRNA on blood lymphocytes help to for identification and subtyping of schizophrenia? Mol Biol Rep 2010; 38:2569-72. [PMID: 21110120 DOI: 10.1007/s11033-010-0396-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2010] [Accepted: 11/08/2010] [Indexed: 10/18/2022]
Abstract
Schizophrenia is one of the neuropathological disorders, which are associated with dopamine and its receptors. In recent years, it has been shown that mRNA of D3, D4 and D5 dopamine receptor (DRD3, DRD4, DRD5) subtypes is expressed in human peripheral blood lymphocytes (PBL). A total 55 schizophrenic patients and 51 healthy subjects were included in the study to investigate the levels of DRD3 mRNA in PBL of schizophrenic patients and whether DRD3 mRNA level in PBL can serve as peripheral marker for schizophrenia. RNA was isolated from lymphocytes of both groups and reverse transcriptase polymerase chain reaction (RT-PCR) was performed for DRD3 mRNA. We found a significant difference in PBL DRD3 mRNA levels among schizophrenia subtypes (P=0.030) while no difference was detected between control subjects and schizophrenics. We concluded that the levels of DRD3 mRNA can help understanding and severity of clinical manifestations in schizophrenia.
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Frieling H, Römer KD, Scholz S, Mittelbach F, Wilhelm J, De Zwaan M, Jacoby GE, Kornhuber J, Hillemacher T, Bleich S. Epigenetic dysregulation of dopaminergic genes in eating disorders. Int J Eat Disord 2010; 43:577-83. [PMID: 19728374 DOI: 10.1002/eat.20745] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE The pathophysiology of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN) has been linked to an impaired dopaminergic neurotransmission, still the origin of this disturbance remains unknown. The aim of the present study was, therefore, to evaluate whether the expression of dopaminergic genes is altered in the blood of patients suffering from eating disorders and if these alterations can be explained by changes in the promoter specific DNA methylation of the genes. METHOD We used quantitative real-time PCR to measure both the expression and the promoter specific DNA methylation of the dopamine transporter (DAT), and the D2 (DRD2) and D4 receptor (DRD4) gene in the blood of 46 patients (22 AN, 24 BN) and 30 healthy controls. RESULTS Patients showed an elevated expression of DAT mRNA when compared with the controls and a downregulation of the DRD₂ expression. The upregulation of the DAT gene was accompanied by a hypermethylation of the gene's promoter in the AN and BN group while a significant hypermethylation of the DRD₂ promoter was only present in the AN group. No differences in expression or methylation were found for the other dopamine receptors investigated. DISCUSSION Our study shows a disturbed expression of dopaminergic genes that is accompanied by a dysregulation of the epigenetic DNA methylation. Further studies are necessary to provide more insight into the epigenetic dysregulation of the dopaminergic neurotransmission in the pathophysiology of eating disorders.
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Affiliation(s)
- Helge Frieling
- Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Erlangen, Germany.
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37
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Expression of NMDA receptor subunits in human peripheral blood lymphocytes in opioid addiction. Eur J Pharmacol 2010; 638:29-32. [DOI: 10.1016/j.ejphar.2010.04.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 03/15/2010] [Accepted: 04/13/2010] [Indexed: 11/21/2022]
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Sedaghati M, Vousooghi N, Goodarzi A, Yaghmaei P, Mokri A, Zarrindast MR. Expression of NR3B but not NR2D subunit of NMDA receptor in human blood lymphocytes can serve as a suitable peripheral marker for opioid addiction studies. Eur J Pharmacol 2010; 633:50-4. [PMID: 20153313 DOI: 10.1016/j.ejphar.2010.02.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Revised: 12/17/2009] [Accepted: 02/02/2010] [Indexed: 11/18/2022]
Abstract
Glutamate is critically involved in opioid addiction. It has been suggested that neurotransmitter receptors expression in peripheral blood lymphocytes may reflect brain status. In the present study, using Real-time PCR, the mRNA expression of NR2D and NR3B subunits of NMDA glutamate receptor has been investigated in peripheral blood lymphocytes of four groups each comprising of 25 male individuals: opioid addicts, methadone maintained patients, long-term abstinent former opioid addicts, and non-addicted control subjects. We found that NR2D subunit mRNA expression was not changed in all three test groups in comparison to control subjects. However, the NR3B mRNA expression was significantly up-regulated by the factors 9.11 (P<0.001), 10.07 (P<0.001) and 4.08 (P<0.05) in abstinent, addicted and methadone maintained subjects, respectively relative to control group. As a conclusion, our data indicate that the transcriptional level of the NR2D subunit of NMDA receptor is not regulated by chronic opioid addiction. However, it seems that the over-expression of NR3B subunit of NMDA receptor is a long lasting result of opioid abuse. In addition, considerable decrease in the up-regulated state of the NR3B subunit by methadone may represent another benefit of methadone therapy for opioid addicts and may serve as a suitable marker to evaluate the successfulness of therapy.
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Affiliation(s)
- Mahmoud Sedaghati
- Science and Research Branch of Islamic Azad University, Tehran, Iran; Sina Cellular and Molecular Research Center, Tehran, Iran
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Abnormal adenosine and dopamine receptor expression in lymphocytes of Lesch-Nyhan patients. Brain Behav Immun 2009; 23:1125-31. [PMID: 19635551 DOI: 10.1016/j.bbi.2009.07.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2009] [Revised: 07/21/2009] [Accepted: 07/21/2009] [Indexed: 11/27/2022] Open
Abstract
Self-injurious behavior is the most outstanding feature of Lesch-Nyhan syndrome and has recently been ascribed to an obsessive-compulsive behavior. Lesch-Nyhan syndrome results from the complete enzyme deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) but the link between abnormal purine metabolism and its neurological and behavioral manifestations remains largely unknown. Previous studies led us to hypothesize that adenosine and dopamine receptor expression could be altered in HPRT-deficient cells. To test this hypothesis, we examined mRNA expressions of adenosine (ADORA2A and ADORA2B) and dopamine receptors (DRD1 and DRD2 like), and dopamine transporter (DAT1) in peripheral blood lymphocytes (PBLs) from Lesch-Nyhan patients. We also examined the influence of hypoxanthine in these expressions. As compared to normal PBLs, both ADORA2A and DRD5 expression were abnormal in PBLs from Lesch-Nyhan patients. In contrast, DAT1 expression was similar to control values in HPRT deficient PBLs. These results indicate an abnormal adenosine and dopamine receptor expression in HPRT-deficient cells and suggest disrupted adenosine and dopamine neurotransmission may have a significant role in the pathogenesis of the neurological manifestations of Lesch-Nyhan syndrome.
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40
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Ahangari G, Shariati G, Asadi M, Ostadali M, Ahmadkhaniha H. Novel Mutation Detection of Regulatory Molecule Dopamine Gene Receptors (D1–D5) Encoding Analysis on Human Peripheral Blood Lymphocytes in Schizophrenia Patients. EUR J INFLAMM 2009. [DOI: 10.1177/1721727x0900700304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
There is much evidence which highlights the involvement of the dopamine system in the pathophysiology of schizophrenia. Recently, there have been reports of detected mutations in dopamine gene receptors in genomic DNA of schizophrenia. In this study, we attempt to determine whether there is mutation in encoding dopamine receptor. The PBMC was separated from whole blood by Ficoll-hypaque; the total cellular RNA was extracted and the cDNA was synthesized. This process followed by real-time PCR using primer pairs specific for five dopamine receptor mRNAs and β-actin as internal control. The results show the presence of all types of dopamine receptor types in lymphocytes. The mutational analysis of the obtained PCR products for the respective dopamine receptor fragments were analyzed by sequenced capillary system. The results presented in this study confirm the high frequency of mutations in dopamine gene receptor DRD5 in schizophrenia patients. Mutational amino acid changes in dopamine gene receptors of DR2, DR3, DR4 but not DR1 are also shown. In conclusion, this is the first report of such complete mutational analyses in all dopamine gene receptors. Moreover, we found new mutations and 80% frequency of mutations in DRD5. These data further strengthen the argument for the role of dopamine gene receptor mutations in the pathogenesis of schizophrenia.
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Affiliation(s)
- G. Ahangari
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran
| | - G.H. Shariati
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology (NIGEB), Tehran
- Department of Genetics & Biology, Jundishahpour Medical Science University, Ahwaz
| | - M.R. Asadi
- Department of Psychiatry, Rozheh Hospital, Tehran Medical University, Tehran
| | - M.R. Ostadali
- Department of Hematology, Oncology and Stem Cell Transplantation, Shariati Hospital, Tehran Medical University, Tehran
| | - H.R. Ahmadkhaniha
- Tehran Psychiatric Institute, Iran University of Medical Sciences, Tehran; World Health Organization Collaborating Center for Mental Health, Tehran, Iran
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Vousooghi N, Goodarzi A, Roushanzamir F, Sedaghati T, Zarrindast MR, Noori-Daloii MR. Expression of mu opioid receptor splice variants mRNA in human blood lymphocytes: A peripheral marker for opioid addiction studies. Int Immunopharmacol 2009; 9:1016-20. [DOI: 10.1016/j.intimp.2009.02.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Revised: 02/25/2009] [Accepted: 02/26/2009] [Indexed: 10/21/2022]
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Goodarzi A, Vousooghi N, Sedaghati M, Mokri A, Zarrindast MR. Dopamine receptors in human peripheral blood lymphocytes: changes in mRNA expression in opioid addiction. Eur J Pharmacol 2009; 615:218-22. [PMID: 19445922 DOI: 10.1016/j.ejphar.2009.04.060] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Revised: 04/24/2009] [Accepted: 04/29/2009] [Indexed: 11/17/2022]
Abstract
Gradual adaptations of the brain to repeated drug exposure may induce addiction. Brain mesolimbic dopaminergic pathway is the site of the effect of addictive drugs. The dopamine receptors in peripheral blood lymphocytes may reflect the status of homologous brain receptors. In the present study, the effects of opioid addiction on mRNA expression of dopamine D(3), D(4) and D(5) receptors in human peripheral blood lymphocytes were investigated, using a real-time PCR method. Four groups each comprising 30 individuals were enrolled in the study: opioid addicted, methadone maintained, long-term abstinent and normal subjects. The results indicated that dopamine D(3) receptor mRNA expression was increased in addicted and methadone maintained subjects by a factor of 1.74 and 1.98, respectively, but no change was observed in the abstinent group. The dopamine D(4) receptor mRNA expression was reduced in abstinent and addicted subjects (but not in the methadone group) and reached 0.44 and 0.53 the amount of the control group, respectively. Expression of dopamine D(5) receptor mRNA showed a significant reduction in abstinent subjects (0.41 the amount of the control group). However, in the addicted and methadone maintained groups, the change of expression level was not statistically significant. It can be concluded that persisting deficiency of dopamine D(4) and D(5) receptors may be a risk factor urging individuals to addiction, and methadone may exert its therapeutic effects through normalizing mRNA expression of these receptors. The dopamine D(3) receptor may have a negative feedback role in addiction; however, we have no explanation for the persisting up-regulation of this receptor in methadone subjects.
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Affiliation(s)
- Ali Goodarzi
- Institute for Cognitive Sciences Studies, Tehran, Iran
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43
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Kirillova GP, Hrutkay RJ, Shurin MR, Shurin GV, Tourkova IL, Vanyukov MM. Dopamine receptors in human lymphocytes: radioligand binding and quantitative RT-PCR assays. J Neurosci Methods 2008; 174:272-80. [PMID: 18721826 DOI: 10.1016/j.jneumeth.2008.07.018] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2008] [Revised: 07/22/2008] [Accepted: 07/22/2008] [Indexed: 10/21/2022]
Abstract
Analysis of dopamine receptors (DR) in lymphocytes of the human peripheral blood mononuclear cell (PBMC) fraction is an attractive tool for evaluation of functional properties of dopaminergic function underlying variation in complex psychological/psychopathological traits. Receptor binding assays (RBAs) with selective radioligands, which are widely used in CNS studies, have not produced consistent results when applied to isolated PBMC. We tested the assay conditions that could be essential for detection of DR in human PBMC and their membrane preparations. Using [(3)H]SCH23390, a dopamine D1-like receptor antagonist, we demonstrated the presence of two binding sites in PBMC-derived membrane fraction. One of them is characterized by the K(d) value consistent with that reported for D5 dopamine receptors in human lymphocytes, whereas the other K(d) value possibly corresponds to serotonin receptor(s). Although D5 receptor binding sites in PBMC membranes could be characterized by binding assays, the low protein expression and the large volume of blood needed for membrane preparation render the binding method impracticable for individual phenotyping. In contrast, real-time RT-PCR may be used for this purpose, contingent on the relationship between DR expression in the brain and in lymphocytes. The expression of the DRD2-DRD5 genes, as detected by this method, varied widely among samples, whereas the DRD1 expression was not detected. The expression levels were comparable with those in the brain for DRD3 and DRD4, and were significantly lower for DRD2 and DRD5.
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Affiliation(s)
- Galina P Kirillova
- Center for Education and Drug Abuse Research, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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44
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Kakiuchi C, Ishiwata M, Nanko S, Ozaki N, Iwata N, Umekage T, Tochigi M, Kohda K, Sasaki T, Imamura A, Okazaki Y, Kato T. Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:557-64. [PMID: 18081029 DOI: 10.1002/ajmg.b.30643] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
The contribution of genetic factors to schizophrenia is well established and recent studies have indicated several strong candidate genes. However, the pathophysiology of schizophrenia has not been totally elucidated yet. To date, studies of monozygotic twins discordant for schizophrenia have provided insight into the pathophysiology of this illness; this type of study can exclude inter-individual variability and confounding factors such as effects of drugs. In this study we used DNA microarray analysis to examine the mRNA expression patterns in the lymphoblastoid (LB) cells derived from two pairs of monozygotic twins discordant for schizophrenia. From five independent replicates for each pair of twins, we selected five genes, which included adrenomedullin (ADM) and selenoprotein X1 (SEPX1), as significantly changed in both twins with schizophrenia. Interestingly, ADM was previously reported to be up-regulated in both the LB cells and plasma of schizophrenic patients, and SEPX1 was included in the list of genes up-regulated in the peripheral blood cells of schizophrenia patients by microarray analysis. Then, we performed a genetic association study of schizophrenia in the Japanese population and examined the copy number variations, but observed no association. These findings suggest the possible role of ADM and SEPX1 as biomarkers of schizophrenia. The results also support the usefulness of gene expression analysis in LB cells of monozygotic twins discordant for an illness.
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Affiliation(s)
- Chihiro Kakiuchi
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan
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Biermann T, Bönsch D, Reulbach U, Kornhuber J, Bleich S. Dopamine and N-methyl-D-aspartate receptor expression in peripheral blood of patients undergoing alcohol withdrawal. J Neural Transm (Vienna) 2007; 114:1081-4. [PMID: 17370105 DOI: 10.1007/s00702-007-0661-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2006] [Accepted: 02/09/2007] [Indexed: 12/01/2022]
Abstract
The aim of the present pilot study was to explore whether a change in cerebral receptors can be demonstrated in human peripheral blood lymphocytes during alcohol withdrawal. Dopamine (D1 and D2) and NMDA (1 and 2B) receptor expressions of 14 male patients suffering from alcohol-dependency were assessed through quantitative RT-PCR. A significant difference in D1 receptor expression (T = 2.361; p = 0.035) in terms of up-regulation could be shown, though there were no significant changes concerning D2, NMDA1 or NMDA2B receptor expression.
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Affiliation(s)
- T Biermann
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
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Vogel M, Busse S, Freyberger HJ, Grabe HJ. Dopamine D3 receptor and schizophrenia: A widened scope for the immune hypothesis. Med Hypotheses 2006; 67:354-8. [PMID: 16540254 DOI: 10.1016/j.mehy.2006.01.044] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2006] [Accepted: 01/30/2006] [Indexed: 11/30/2022]
Abstract
Schizophrenia may be related to immunity as is suggested by many findings of altered immune parameters in schizophrenic patients. How immune alterations might be involved in the emergence of psychosis is still unclear. Clearly, however, the dopamine hypothesis has been confirmed in recent studies, which implies a crucial role for dopamine and the dopamine D2 receptor (D2R) within the pathogenesis of schizophrenia. The Dopamine D3 receptor (D3R) is considered to have autoreceptor properties modulating the synthesis and release of dopamine, thereby possibly antagonizing the dopamine D2-receptor-mediated effects of dopamine and has been found reduced in schizophrenic patients during acute psychosis and increasing in the advent of negative schizophrenic symptoms. Immune parameters apparently influence the expression of dopamine receptors by means of their capability to induce regulatory factors involved in the expression of dopamine receptor subtypes, such as the neurotrophins, associations of which with psychosis have been reported repeatedly. Here, we propose a hypothesis of immune alterations that influence the production of distinct neurotrophins such as BDNF and NGF that, as animal studies suggest, influence the expression of dopamine receptor subtypes. This mechanism could result in a decrease of D3R and a consecutive relative preponderance of D2R and thereby connect immune alterations and schizophrenia.
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Affiliation(s)
- Matthias Vogel
- Department of Psychiatry and Psychotherapy, Ernst-Moritz-Arndt-University, Greifswald, Rostocker Chaussee 70, D-18437 Stralsund, Germany.
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Boneberg EM, von Seydlitz E, Pröpster K, Watzl H, Rockstroh B, Illges H. D3 dopamine receptor mRNA is elevated in T cells of schizophrenic patients whereas D4 dopamine receptor mRNA is reduced in CD4+ -T cells. J Neuroimmunol 2005; 173:180-7. [PMID: 16376996 DOI: 10.1016/j.jneuroim.2005.11.018] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2005] [Accepted: 11/22/2005] [Indexed: 12/15/2022]
Abstract
The expression of dopamine receptors was examined in purified human neutrophils, monocytes, B cells, natural killer cells and CD4+ - and CD8+ -T lymphocytes by RT-PCR. In healthy subjects, D1 and D2 receptors were not expressed in leukocytes. Real Time PCR for dopamine receptors D3 and D4 disclosed that D3 receptors are expressed in T cells and natural killer cells and D4 receptors in CD4+ -T cells. The comparison of schizophrenic patients with sex- and age-matched controls revealed a significantly higher expression of D3 receptor mRNA in T cells of schizophrenic patients, whereas D4 receptor mRNA in CD4+ -T cells was downregulated.
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Affiliation(s)
- Eva-Maria Boneberg
- Biotechnology Institute Thurgau, Konstanzer Strasse 19, 8274 Taegerwilen, Switzerland.
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Besser MJ, Ganor Y, Levite M. Dopamine by itself activates either D2, D3 or D1/D5 dopaminergic receptors in normal human T-cells and triggers the selective secretion of either IL-10, TNFalpha or both. J Neuroimmunol 2005; 169:161-71. [PMID: 16150496 DOI: 10.1016/j.jneuroim.2005.07.013] [Citation(s) in RCA: 161] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2005] [Accepted: 07/25/2005] [Indexed: 11/18/2022]
Abstract
The neurotransmitter dopamine on its own increased significantly TNFalpha and IL-10 secretion by resting normal-human T-cells, and induced approximately 5-fold elevation of the corresponding mRNA's, without affecting IFNgamma and IL-4. Using seven highly selective dopamine-receptor (DR) agonists and antagonists we found that TNFalpha-upregulation, evident after 24 h, was mediated by D3R and D1/D5R while IL-10-upregulation, evident after 72 h, was mediated by D2R and D1/D5R. We confirmed the expression of D2R and D3R in these human T cells. Dopamine's unique ability to trigger a selective secretion of either TNFalpha only (via D3R) or IL-10 only (via D2R) or both (via D1/D5R), differs from the robust and non-selective cytokine-secretion induced by 'classical' TCR-activation, and as such may have important beneficial or detrimental implications in various immunological and neurological diseases/injuries/cancers.
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Affiliation(s)
- Michal J Besser
- Department of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel
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Abstract
It is regularly thought that human complex disorder susceptibility genes show differences in gene expression between normal and pathologic tissues. Thus, differences of transcript amounts could be indicative of complex disorder susceptibility loci and, therefore, be used for the discovery or the validation of human susceptibility genes to complex disorders/traits. Whether human complex disorder susceptibility genes effectively display differences in transcript amounts was tested by meta-analysis of the published literature comparing transcript amounts of well-validated human susceptibility genes to complex traits/disorders. A total of 94 gene-disease associations, which were studied in at least three independent studies and showed strong evidence of positive association, were analyzed. For 23 out of these 94 well-validated gene-disease associations, 120 gene expression studies comparing normal and pathologic human tissues were found. For 60 out of these 120 gene expression studies, the difference of level expression between normal and pathologic human tissues was statistically significant. This result was highly significant, as only 6 significant results were expected randomly under the null hypothesis (P < 10(-112)). A large excess of replication studies were also found, which were in agreement with the original report (P = 6 x 10(-4)). However, the overall level of expression change between normal and pathologic human tissues was relatively moderate, because only 36 (60%) and 19 (31.6%) out of the 62 statistically significant gene expression studies reached 2- or 3-fold changes in expression level, respectively. The present meta-analysis confirms statistical differences of expression levels between normal and pathologic human tissues for human susceptibility genes to complex traits/disorders. However, the levels of differences in transcript amounts appear to be relatively weak. These findings rationalize the use of gene expression for the discovery/validation of human susceptibility genes, but the weak differences of expression typically found should be taken into account for the design of such studies.
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Vogel M, Pfeifer S, Schaub RT, Grabe HJ, Barnow S, Freyberger HJ, Cascorbi I. Decreased levels of dopamine D3 receptor mRNA in schizophrenic and bipolar patients. Neuropsychobiology 2005; 50:305-10. [PMID: 15539862 DOI: 10.1159/000080958] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Previous studies found an elevation of the dopamine D3 receptor (DRD3) mRNA as determined in peripheral lymphocytes in schizophrenic patients. The aim of this study was to test the hypothesis of elevated DRD3 mRNA in schizophrenia compared to bipolar disorder. Twenty-four patients, 13 schizophrenic and 11 bipolar, were included according to DSM-IV criteria. Psychometric measures were conducted using the Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Brief Psychiatric Rating Scale, Montgomery-Asberg Depression Rating Scale and Young Mania Rating Scale. mRNA was isolated from lymphocytes of venous blood samples and DRD3 mRNA was quantified using real-time reverse transcription PCR. We found a decrease in DRD3 mRNA in 13 schizophrenic (p = 0.009) and 11 bipolar (p = 0.023) patients as compared to controls. Medication history and severity of positive symptoms did not significantly influence DRD3 expression. Higher levels of DRD3 mRNA were correlated with negative schizophrenic symptoms. Interestingly, after treatment of patients with antipsychotics, DRD3 mRNA levels increased to similar levels as those of healthy controls. Bipolar patients, however, showed a slower increase in DRD3 mRNA levels after 3 weeks of therapy. Our findings suggest that the expression of DRD3 mRNA is reduced in schizophrenia and bipolar disorder, supporting the hypothesis of distorted homeostasis of dopamine receptor subtypes in psychotic disorder. The observed diminution was not specific for schizophrenia but also for bipolar disorder requiring further analysis of the regulatory factors involved in dopamine receptor subtype expression.
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Affiliation(s)
- Matthias Vogel
- Department of Psychiatry and Psychotherapy, Ernst Moritz Arndt University, Greifswald, Germany.
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