|
1
|
Köhler-Forsberg O, Keers R, Uher R, Hauser J, Maier W, Rietschel M, McGuffin P, Farmer AE, Aitchison KJ, Mors O. Dimensions of temperament and character as predictors of antidepressant discontinuation, response and adverse reactions during treatment with nortriptyline and escitalopram. Psychol Med 2023; 53:2522-2530. [PMID: 34763734 DOI: 10.1017/s003329172100444x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Personality traits may predict antidepressant discontinuation and response. However, previous studies were rather small, only explored a few personality traits and did not include adverse drug effects nor the interdependency between antidepressant discontinuation patterns and response. METHODS GENDEP included 589 patients with unipolar moderate-severe depression treated with escitalopram or nortriptyline for 12 weeks. Seven personality dimensions were measured using the self-reported 240-item Temperament and Character Inventory-Revised (TCI-R). We applied Cox proportional models to study discontinuation patterns, logistic and linear regression to investigate response and remission after 8 and 12 weeks, and mixed-effects linear models regarding time-varying treatment response and adverse drug reactions. RESULTS Low harm avoidance, low cooperativeness, high self-transcendence and high novelty seeking were associated with higher risks for antidepressant discontinuation, independent of depressed mood, adverse drug reactions, drug, sex and age. Regression analyses showed that higher novelty seeking and cooperativeness scores were associated with a greater likelihood of response and remission after 8 and 12 weeks, respectively, but we found no correlations with response in the mixed-effects models. Only high harm avoidance was associated with more self-reported adverse effects. CONCLUSIONS This study, representing the largest investigation between several personality traits and response to two different antidepressants, suggests that correlations between personality traits and antidepressant treatment response may be confounded by differential rates of discontinuation. Future trials on personality in the treatment of depression need to consider this interdependency and study whether interventions aiming at improving compliance for some personality types may improve response to antidepressants.
Collapse
Affiliation(s)
- Ole Köhler-Forsberg
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Robert Keers
- Department of Biological and Experimental Psychology, Queen Mary University of London, Mile End, London, UK
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Rudolf Uher
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
| | - Joanna Hauser
- Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Wolfgang Maier
- Department of Psychiatry, University of Bonn, Bonn, Germany
| | - Marcella Rietschel
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Peter McGuffin
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Anne E Farmer
- Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Katherine J Aitchison
- Department of Psychiatry, Department of Medical Genetics, University of Alberta, Edmonton, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada
| | - Ole Mors
- Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| |
Collapse
|
|
2
|
Jukić T, Margetić BA, Jakšić N, Boričević V. Personality differences in patients with and without gallstones. J Psychosom Res 2023; 169:111322. [PMID: 37018955 DOI: 10.1016/j.jpsychores.2023.111322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 04/07/2023]
Abstract
OBJECTIVE Presence of gallstones is associated with a range of risk factors that have previously shown associations with personality traits. Our aim was to assess the differences in personality traits between the patients with and without gallstones. METHODS This study used a case-control design with 308 participants from the general population, 68.2% female, mean age 49.2 (SD 9.24) years, of whom 154 (50%) participants had asymptomatic gallstones. Personality was assessed with the Temperament and Character Inventory - Revised - 140 (TCI-R-140) and depression with the Center for Epidemiological Study of Depression Scale (CESD). Cut-off ≥16 on the CES-D was used as an exclusion criterion. Subjects were also checked for metabolic risk factors and sociodemographic characteristics. RESULTS The group with gallstones had significantly more pronounced metabolic risk factors and higher prevalence of smoking and alcohol usage in comparison with the group without gallstones. This group also exhibited higher temperament dimension Harm avoidance (HA) and lower character dimension Self-directedness (SD). Metabolic variables differed based on character dimension Cooperativeness (CO), smoking based on temperament dimensions Novelty seeking (NS) and HA, and alcohol usage on dimension NS within the gallstones group. In the logistic regression, controlled for smoking, alcohol usage and metabolic variables, temperament dimension HA was shown to be a significant predictor of the presence of gallstones. CONCLUSION Our findings indicate that personality may be associated with the presence of gallstones. Future longitudinal studies addressing the complex interplay of personality traits, psychological mechanisms and the associated behavioral, metabolic and neurobiological factors, are needed.
Collapse
Affiliation(s)
- Tatjana Jukić
- Neuropsychiatric Hospital Dr. Ivan Barbot, Popovaca, Croatia
| | - Branka Aukst Margetić
- Department of Psychiatry, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia; School of Medicine, University of Zagreb, Zagreb, Croatia; Croatian Catholic University, Zagreb, Croatia.
| | - Nenad Jakšić
- Department of Psychiatry and Psychological Medicine, University Hospital Center Zagreb, Zagreb, Croatia
| | | |
Collapse
|
|
3
|
Beheshti M, Rabiei N, Taghizadieh M, Eskandari P, Mollazadeh S, Dadgostar E, Hamblin MR, Salmaninejad A, Emadi R, Mohammadi AH, Mirazei H. Correlations between single nucleotide polymorphisms in obsessive-compulsive disorder with the clinical features or response to therapy. J Psychiatr Res 2023; 157:223-238. [PMID: 36508934 DOI: 10.1016/j.jpsychires.2022.11.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/08/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric disorder, in which the patient endures intrusive thoughts or is compelled to perform repetitive or ritualized actions. Many cases of OCD are considered to be familial or heritable in nature. It has been shown that a variety of internal and external risk factors are involved in the pathogenesis of OCD. Among the internal factors, genetic modifications play a critical role in the pathophysiological process. Despite many investigations performed to determine the candidate genes, the precise genetic factors involved in the disease remain largely undetermined. The present review summarizes the single nucleotide polymorphisms that have been proposed to be associated with OCD symptoms, early onset disease, neuroimaging results, and response to therapy. This information could help us to draw connections between genetics and OCD symptoms, better characterize OCD in individual patients, understand OCD prognosis, and design more targeted personalized treatment approaches.
Collapse
Affiliation(s)
- Masoumeh Beheshti
- Pathophysiology Laboratory, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women's Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Pariya Eskandari
- Department of Biology, School of Basic Sciences, University of Guilan, Rasht, Iran
| | - Samaneh Mollazadeh
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Ehsan Dadgostar
- Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran; Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa
| | - Arash Salmaninejad
- Regenerative Medicine, Organ Procurement and Transplantation Multi Disciplinary Center, Razi Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran; Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Raziye Emadi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran.
| | - Amir Hossein Mohammadi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| | - Hamed Mirazei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
|
4
|
Barbagallo F, Cucinella L, Tiranini L, Martini E, Bosoni D, Molinaro P, Battista F, Albani F, Calogero AE, Nappi RE. Relationship between personality traits and sexual function in symptomatic postmenopausal women. Maturitas 2022; 166:50-57. [PMID: 36057183 DOI: 10.1016/j.maturitas.2022.08.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 07/06/2022] [Accepted: 08/19/2022] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Female sexual function relies on a complex interplay of physical, psychosocial, and neurobiological factors. Over the last decades, increasing attention has been paid to the influence of personality traits on general health and many aspects of quality of life, including sexuality. OBJECTIVE To assess whether dimensions of the personality are related to the domains of sexual function (desire, arousal, lubrication, orgasm, satisfaction, and pain) in symptomatic postmenopausal women. Mood was also investigated to explore its association with female sexual dysfunction (FSD). METHODS Validated questionnaires to assess sexual function [the Female Sexual Functioning Index (FSFI)], mood [the State-Anxiety Inventory (STAI), and Zung Self Rating Depression Scale (SDS)], and personality traits [the Tridimensional Personality Questionnaire (TPQ)] were filled in by 130 early postmenopausal women experiencing hot flushes (≥30/week). RESULTS 61.5 % (n = 80) of the women had an FSFI total score lower than 26.55, the standard cut-off for FSD. A clinical state of anxiety was present in 53.8 % (n = 70), whereas only 12.3 % (n = 16) showed clinically relevant depressive symptoms. According to the FSFI cut-off score, women with sexual disorders had statistically significantly higher levels of anxiety, depression (p < 0.001 for both), and harm avoidance (HA) (p = 0.004) than women without such disorders. Significantly higher levels of anxiety were found in women in the lower quartile (LQ) of the distribution of the total FSFI score than in women in both the interquartile range (IQR) and in the upper quartile (UQ) (p < 0.05). Moreover, women in the UQ had a lower grade of depression and HA than others (p < 0.05). The Sobel test showed that the personality trait HA significantly mediated the relationship between anxiety and FSFI total score (Z = -2.19, p < 0.05) and between depression and FSFI total score (Z = -2.35, p < 0.05). CONCLUSIONS The present data suggest the personality trait HA is relevant to sexual function and mediates the impact of mood on FSD in symptomatic menopausal women. In clinical practice, the use of validated psychometric tools for mood screening is useful to establish appropriate diagnosis and treatment of sexual disorders in menopausal women. Moreover, the assessment of personality traits could provide additional information that directs clinicians towards an increasingly tailored and multidimensional treatment of FSD.
Collapse
Affiliation(s)
- Federica Barbagallo
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Laura Cucinella
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Lara Tiranini
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Ellis Martini
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy
| | - David Bosoni
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Pietro Molinaro
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Federica Battista
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Francesca Albani
- Gynecological Endocrinology Clinic, Unit of Internal Medicine and Endocrinology, IRCCS Maugeri, Pavia, Italy
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Rossella E Nappi
- Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS San Matteo Foundation, Pavia, Italy; Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
| |
Collapse
|
|
5
|
Fritz N, Berens S, Dong Y, Martínez C, Schmitteckert S, Houghton LA, Goebel-Stengel M, Wahl V, Kabisch M, Götze D, D’Amato M, Zheng T, Röth R, Mönnikes H, Tesarz J, Engel F, Gauss A, Raithel M, Andresen V, Keller J, Frieling T, Pehl C, Stein-Thöringer C, Clarke G, Kennedy PJ, Cryan JF, Dinan TG, Quigley EMM, Spiller R, Beltrán C, Madrid AM, Torres V, Mayer EA, Sayuk G, Gazouli M, Karamanolis G, Bustamante M, Estivil X, Rabionet R, Hoffmann P, Nöthen MM, Heilmann-Heimbach S, Schmidt B, Franke A, Lieb W, Herzog W, Boeckxstaens G, Wouters MM, Simrén M, Rappold GA, Vicario M, Santos J, Schaefert R, Lorenzo-Bermejo J, Niesler B. The serotonin receptor 3E variant is a risk factor for female IBS-D. J Mol Med (Berl) 2022; 100:1617-1627. [PMID: 36121467 PMCID: PMC9592668 DOI: 10.1007/s00109-022-02244-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/18/2022] [Accepted: 08/04/2022] [Indexed: 12/14/2022]
Abstract
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.
Collapse
Affiliation(s)
- Nikola Fritz
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Sabrina Berens
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Yuanjun Dong
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Cristina Martínez
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.420395.90000 0004 0425 020XInstitut de Recerca Biomèdica de Lleida (IRBLleida), Lleida, Spain ,Lleida Institute for Biomedical Research Dr, Pifarré Foundation (IRBLleida), Lleida, Spain
| | - Stefanie Schmitteckert
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Lesley A. Houghton
- grid.443984.60000 0000 8813 7132University of Leeds, St. James’s University Hospital, Leeds, UK ,grid.417467.70000 0004 0443 9942Mayo Clinic, Jacksonville, FL USA
| | - Miriam Goebel-Stengel
- grid.411544.10000 0001 0196 8249Department of Psychosomatic Medicine, University Hospital Tübingen, Tübingen, Germany ,Department of Internal Medicine and Gastroenterology, HELIOS Clinic Rottweil, Rottweil, Germany
| | - Verena Wahl
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Maria Kabisch
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Dorothea Götze
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Mauro D’Amato
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden ,grid.420175.50000 0004 0639 2420Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Bilbao, Derio Spain ,grid.424810.b0000 0004 0467 2314IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Tenghao Zheng
- grid.4714.60000 0004 1937 0626Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Ralph Röth
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany
| | - Hubert Mönnikes
- grid.461755.40000 0004 0581 3852Martin-Luther-Hospital, Berlin, Germany
| | - Jonas Tesarz
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Felicitas Engel
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Annika Gauss
- grid.7700.00000 0001 2190 4373Department of Gastroenterology, Infectious Diseases and Intoxications, Heidelberg University, Heidelberg, Germany
| | - Martin Raithel
- grid.5330.50000 0001 2107 3311University of Erlangen, Erlangen, Germany
| | - Viola Andresen
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | - Jutta Keller
- grid.414844.90000 0004 0436 8670Israelitisches Krankenhaus, Hamburg, Germany
| | | | | | | | - Gerard Clarke
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Paul J. Kennedy
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - John F. Cryan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Timothy G. Dinan
- grid.7872.a0000000123318773Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork, Ireland ,grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Eamonn M. M. Quigley
- grid.7872.a0000000123318773APC Microbiome Ireland, University College Cork, Cork, Ireland ,grid.63368.380000 0004 0445 0041Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Weill Cornell Medical College, Houston, TX USA
| | - Robin Spiller
- grid.4563.40000 0004 1936 8868Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
| | - Caroll Beltrán
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Ana María Madrid
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Verónica Torres
- grid.412248.90000 0004 0412 9717Gastroenterology Unit, Medicine Department, Hospital Clínico Universidad de Chile, Universidad de Chile, Santiago de Chile, Chile
| | - Emeran A. Mayer
- grid.19006.3e0000 0000 9632 6718Oppenheimer Center for Neurobiology of Stress, University of California, Los Angeles, CA USA
| | - Gregory Sayuk
- grid.4367.60000 0001 2355 7002Washington University School of Medicine, St. Louis, MO USA
| | - Maria Gazouli
- grid.5216.00000 0001 2155 0800Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George Karamanolis
- grid.5216.00000 0001 2155 0800Academic Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Laikon General Hospital, Athens, Greece
| | - Mariona Bustamante
- grid.11478.3b0000 0004 1766 3695CRG, Centre for Genomic Regulation, Barcelona, Spain ,grid.434607.20000 0004 1763 3517ISGlobal, Barcelona, Spain
| | - Xavier Estivil
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Raquel Rabionet
- grid.5841.80000 0004 1937 0247Department of Genetics, Microbiology and Statistics, Faculty of Biology, IBUB, Universitat de Barcelona, CIBERER, IRSJD, Barcelona, Spain
| | - Per Hoffmann
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | - Markus M. Nöthen
- grid.435715.10000 0004 0436 7643Life and Brain Center, Bonn, Germany
| | | | - Börge Schmidt
- grid.410718.b0000 0001 0262 7331Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany
| | - André Franke
- Institute of Clinical Molecular Biology, Kiel, Germany
| | - Wolfgang Lieb
- grid.417834.dInstitute of Epidemiology, Kiel, Germany
| | - Wolfgang Herzog
- grid.5253.10000 0001 0328 4908Department of General Internal Medicine and Psychosomatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Guy Boeckxstaens
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Mira M. Wouters
- grid.410569.f0000 0004 0626 3338TARGID, University Hospital Leuven, Louvain, Belgium
| | - Magnus Simrén
- grid.8761.80000 0000 9919 9582Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Gudrun A. Rappold
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
| | - Maria Vicario
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain ,grid.419905.00000 0001 0066 4948Nestlé Institute of Health Sciences, Nestlé Research, Société Des Produits Nestlé S.A, Vers-chez-les-Blanc, Lausanne, Switzerland
| | - Javier Santos
- grid.411083.f0000 0001 0675 8654Institut de Recerca Vall d Hebron, Hospital Vall d Hebron, Passeig de la Vall d Hebron, Barcelona, Spain
| | - Rainer Schaefert
- grid.410567.1Department of Psychosomatic Medicine, Division of Theragnostics, University Hospital Basel, Basel, Switzerland ,grid.6612.30000 0004 1937 0642Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Justo Lorenzo-Bermejo
- grid.7700.00000 0001 2190 4373Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany
| | - Beate Niesler
- grid.5253.10000 0001 0328 4908Institute of Human Genetics, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.5253.10000 0001 0328 4908nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany ,grid.7700.00000 0001 2190 4373Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, Heidelberg, Germany
| |
Collapse
|
|
6
|
Berens S, Dong Y, Fritz N, Walstab J, D'Amato M, Zheng T, Wahl V, Boekstegers F, Bermejo JL, Martinez C, Schmitteckert S, Clevers E, Engel F, Gauss A, Herzog W, Spiller R, Goebel-Stengel M, Mönnikes H, Andresen V, Thomas F, Keller J, Pehl C, Stein-Thöringer C, Clarke G, Dinan TG, Quigley EM, Sayuk G, Simrén M, Tesarz J, Rappold G, van Oudenhove L, Schaefert R, Niesler B. Serotonin type 3 receptor subunit gene polymorphisms associated with psychosomatic symptoms in irritable bowel syndrome: A multicenter retrospective study. World J Gastroenterol 2022; 28:2334-2349. [PMID: 35800179 PMCID: PMC9185212 DOI: 10.3748/wjg.v28.i21.2334] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/21/2021] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Single-nucleotide polymorphisms (SNPs) of the serotonin type 3 receptor subunit (HTR3) genes have been associated with psychosomatic symptoms, but it is not clear whether these associations exist in irritable bowel syndrome (IBS). AIM To assess the association of HTR3 polymorphisms with depressive, anxiety, and somatization symptoms in individuals with IBS. METHODS In this retrospective study, 623 participants with IBS were recruited from five specialty centers in Germany, Sweden, the United States, the United Kingdom, and Ireland. Depressive, anxiety, and somatization symptoms and sociodemographic characteristics were collected. Four functional SNPs - HTR3A c.-42C>T, HTR3B c.386A>C, HTR3C c.489C>A, and HTR3E c.*76G>A - were genotyped and analyzed using the dominant and recessive models. We also performed separate analyses for sex and IBS subtypes. SNP scores were calculated as the number of minor alleles of the SNPs above. The impact of HTR3C c.489C>A was tested by radioligand-binding and calcium influx assays. RESULTS Depressive and anxiety symptoms significantly worsened with increasing numbers of minor HTR3C c.489C>A alleles in the dominant model (F depressive = 7.475, P depressive = 0.006; F anxiety = 6.535, P anxiety = 0.011). A higher SNP score (range 0-6) was linked to a worsened depressive symptoms score (F = 7.710, P-linear trend = 0.006) in IBS. The potential relevance of the HTR3C SNP was corroborated, showing changes in the expression level of 5-HT3AC variant receptors. CONCLUSION We have provided the first evidence that HTR3C c.489C>A is involved in depressive and anxiety symptoms in individuals with IBS. The SNP score indicated that an increasing number of minor alleles is linked to the worsening of depressive symptoms in IBS.
Collapse
Affiliation(s)
- Sabrina Berens
- Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Yuanjun Dong
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Nikola Fritz
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Jutta Walstab
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Mauro D'Amato
- Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio 48160, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao 48001, Spain
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden
| | - Tenghao Zheng
- Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm 17177, Sweden
| | - Verena Wahl
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Felix Boekstegers
- Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
| | - Justo Lorenzo Bermejo
- Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg 69120, Germany
| | - Cristina Martinez
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Av. Alcalde Rovira Roure, Lleida 25198, Spain
| | - Stefanie Schmitteckert
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
| | - Egbert Clevers
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven 3000, Belgium
| | - Felicitas Engel
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Annika Gauss
- Department of Gastroenterology, Infectious Diseases and Intoxications, University of Heidelberg, Heidelberg 69120, Germany
| | - Wolfgang Herzog
- Department of General Internal Medicine and Psychosomatics, Heidelberg University, Heidelberg 69120, Germany
| | - Robin Spiller
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham NG7 2QL, United Kingdom
| | | | - Hubert Mönnikes
- Department of Medicine, Institute of Neurogastroenterology (H.M.), Martin-Luther-Hospital, Belin 14193, Germany
| | - Viola Andresen
- Israelitisches Krankenhaus in Hamburg, Hamburg 22297, Germany
| | - Frieling Thomas
- Internal Medicine II, Helios Klinikum Krefeld, Krefeld 47805, Germany
| | - Jutta Keller
- Israelitisches Krankenhaus Hamburg, Hamburg 22297, Ghana
| | | | | | - Gerard Clarke
- Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland
| | - Timothy G Dinan
- Department of Psychiatry and Neurobehavioral Science, University College Cork, Cork T23, Ireland
| | - Eamonn M Quigley
- Medicine in Digestive Disorders, Department of Medicine, Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist, Houston, TX 77030, United States
| | - Gregory Sayuk
- Division of Gastroenterology, Washington University School of Medicine, Department of Psychiatry, School of Medicine, John Cochran Veteran Affairs Medical Center, St. Louis, MO 63110, United States
| | - Magnus Simrén
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital, Gothenburg SE-41685, Sweden
| | - Jonas Tesarz
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
| | - Gudrun Rappold
- Department of Human Molecular Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg 69120, Germany
- Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany
| | - Lukas van Oudenhove
- Cognitive and Affective Neuroscience Lab, Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03748, United States
- Laboratory for Brain-Gut Axis Studies, Translational Research Center for Gastrointestinal Disorders, Department of Chronic Diseases, Metabolism, and Ageing, KU Leuven, Leuven 3000, Belgium
| | - Rainer Schaefert
- Department of General Internal Medicine and Psychosomatics, Internal Medicine II, University Hospital Heidelberg, Heidelberg 69120, Germany
- Department of Psychosomatic Medicine, Division of Internal Medicine, University Hospital Basel, Basel CH-4031, Switzerland
| | - Beate Niesler
- Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg 69120, Germany
- Department of Human Molecular Genetics, Heidelberg University, Heidelberg 69120, Germany
| |
Collapse
|
|
7
|
Irving H, Turek I, Kettle C, Yaakob N. Tapping into 5-HT 3 Receptors to Modify Metabolic and Immune Responses. Int J Mol Sci 2021; 22:ijms222111910. [PMID: 34769340 PMCID: PMC8584345 DOI: 10.3390/ijms222111910] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 02/07/2023] Open
Abstract
5-hydroxytryptamine type 3 (5-HT3) receptors are ligand gated ion channels, which clearly distinguish their mode of action from the other G-protein coupled 5-HT or serotonin receptors. 5-HT3 receptors are well established targets for emesis and gastrointestinal mobility and are used as adjunct targets in treating schizophrenia. However, the distribution of these receptors is wider than the nervous system and there is potential that these additional sites can be targeted to modulate inflammatory and/or metabolic conditions. Recent progress in structural biology and pharmacology of 5-HT3 receptors have provided profound insights into mechanisms of their action. These advances, combined with insights into clinical relevance of mutations in genes encoding 5-HT3 subunits and increasing understanding of their implications in patient's predisposition to diseases and response to the treatment, open new avenues for personalized precision medicine. In this review, we recap on the current status of 5-HT3 receptor-based therapies using a biochemical and physiological perspective. We assess the potential for targeting 5-HT3 receptors in conditions involving metabolic or inflammatory disorders based on recent findings, underscoring the challenges and limitations of this approach.
Collapse
Affiliation(s)
- Helen Irving
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; (I.T.); (C.K.)
- Correspondence:
| | - Ilona Turek
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; (I.T.); (C.K.)
| | - Christine Kettle
- Department of Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, Bendigo, VIC 3550, Australia; (I.T.); (C.K.)
| | - Nor Yaakob
- Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia;
| |
Collapse
|
|
8
|
Ledermann K, Hasler G, Jenewein J, Sprott H, Schnyder U, Martin-Soelch C. 5'UTR polymorphism in the serotonergic receptor HTR3A gene is differently associated with striatal Dopamine D2/D3 receptor availability in the right putamen in Fibromyalgia patients and healthy controls-Preliminary evidence. Synapse 2020; 74:e22147. [PMID: 31868947 DOI: 10.1002/syn.22147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/12/2019] [Accepted: 12/17/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Extensive literature has investigated the role of serotonin (5-HT) in the control of the central dopamine (DA) systems, and their dysfunction in the pathological conditions. 5-HT stimulates the local DA release in striatal regions via activation of various receptors including serotonin receptor-3 (5-HT3). Several studies have related polymorphisms (SNPs) in the serotonin receptor-3 (HTR3) genes to be associated with the pain modulation and endogenous pain suppression. A few studies suggested a functional role of 5'UTR SNP in the serotonergic receptor HTR3A gene (rs1062613) in the development of the chronic pain and Fibromyalgia syndrome (FMS) in particular. Here, we investigated the effect of a 5'UTR SNP in the serotonergic receptor HTR3A gene (rs1062613) on striatal dopamine D2/D3 receptor (DRD2) availability and reward-associated DA release in response to unpredictable monetary rewards in 23 women with FMS and 17 age-matched healthy female controls. Furthermore, we aimed to examine if SNP rs1062613 is associated with thermal pain and pain tolerance thresholds. METHODS We used PET and [11 C]raclopride to assess the DRD2 availability. In the same participants we used the [11 C]raclopride PET bolus-plus-infusion method to measure the [11 C]raclopride receptor binding potential (ΔBP) between an unpredictable reward condition and a sensorimotor control condition. DRD2 availability and ΔBP were assessed in MRI-based striatal regions of interest. Thermal pain and pain tolerance thresholds were assessed outside the scanner. RESULTS The frequency of SNP rs1062613 genotype differed significantly between groups, indicating that CC homozygotes were more frequent in FMS patients (82.6%) than in healthy controls (41.3%). Our results showed a significant main effect of SNP rs1062613 on [11 C]raclopride binding potential in the right caudate nucleus indicating a higher DRD2 receptor availability for CC-genotype of this SNP. Furthermore, we found a significant group × SNP interaction on [11 C]raclopride binding potential in the right putamen, indicating a higher DRD2 availability in T-carriers compared to CC genotype of SNP rs1062613 in FMS patients, whereas this effect was not present in healthy controls. However, we did not find an influence of SNP rs1062613 on reward-related DA release. In addition, there was no association between SNP rs1062613 and pain threshold or pain tolerance threshold in our data. CONCLUSION These preliminary results indicate that SNP rs1062613 in the serotonergic receptor HTR3A gene possibly modulates the DRD2 receptor availability.
Collapse
Affiliation(s)
- Katharina Ledermann
- Department of Psychology, Unit of Clinical and Health Psychology, University Fribourg, Fribourg, Switzerland.,Department of Consultation-Liaison Psychiatry and Psychosomatics, University Hospital, University of Zurich, Zurich, Switzerland
| | - Gregor Hasler
- Department of Psychology, Unit of Clinical and Health Psychology, University Fribourg, Fribourg, Switzerland
| | - Josef Jenewein
- Department of Consultation-Liaison Psychiatry and Psychosomatics, University Hospital, University of Zurich, Zurich, Switzerland.,Clinic Zugersee, Center for Psychiatry and Psychotherapy, Oberwil-Zug, Switzerland
| | - Haiko Sprott
- University of Zurich and Arztpraxis Hottingen, Zurich, Switzerland
| | | | - Chantal Martin-Soelch
- Department of Psychology, Unit of Clinical and Health Psychology, University Fribourg, Fribourg, Switzerland
| |
Collapse
|
|
9
|
Derksen M, Feenstra M, Willuhn I, Denys D. The serotonergic system in obsessive-compulsive disorder. HANDBOOK OF BEHAVIORAL NEUROSCIENCE 2020. [DOI: 10.1016/b978-0-444-64125-0.00044-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
|
|
10
|
Genetic polymorphisms and their association with brain and behavioural measures in heterogeneous stock mice. Sci Rep 2017; 7:41204. [PMID: 28145470 PMCID: PMC5286500 DOI: 10.1038/srep41204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 12/16/2016] [Indexed: 12/30/2022] Open
Abstract
Although the search for quantitative trait loci for behaviour remains a considerable challenge, the complicated genetic architecture of quantitative traits is beginning to be understood. The current project utilised heterogeneous stock (HS) male mice (n = 580) to investigate the genetic basis for brain weights, activity, anxiety and cognitive phenotypes. We identified 126 single nucleotide polymorphisms (SNPs) in genes involved in regulation of neurotransmitter systems, nerve growth/death and gene expression, and subsequently investigated their associations with changes in behaviour and/or brain weights in our sample. We found significant associations between four SNP-phenotype pairs, after controlling for multiple testing. Specificity protein 2 (Sp2, rs3708840), tryptophan hydroxylase 1 (Tph1, rs262731280) and serotonin receptor 3A (Htr3a, rs50670893) were associated with activity/anxiety behaviours, and microtubule-associated protein 2 (Map2, rs13475902) was associated with cognitive performance. All these genes except for Tph1 were expressed in the brain above the array median, and remained significantly associated with relevant behaviours after controlling for the family structure. Additionally, we found evidence for a correlation between Htr3a expression and activity. We discuss our findings in the light of the advantages and limitations of currently available mouse genetic tools, suggesting further directions for association studies in rodents.
Collapse
|
|
11
|
Celli J, Rappold G, Niesler B. The Human Serotonin Type 3 Receptor Gene (HTR3A-E) Allelic Variant Database. Hum Mutat 2016; 38:137-147. [PMID: 27763704 DOI: 10.1002/humu.23136] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 10/11/2016] [Accepted: 10/15/2016] [Indexed: 12/17/2022]
Abstract
Serotonin type 3 (5-HT3 ) receptors are ligand-gated ion channels formed by five subunits (5-HT3A-E), which are encoded by the HTR3A, HTR3B, HTR3C, HTR3D, and HTR3E genes. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes confer a predisposition to nausea and vomiting during chemotherapy, pregnancy, and following surgery. In addition, different subtypes contribute to neurogastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as comorbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS and are beneficial in the treatment of psychiatric diseases. Several case-control and pharmacogenetic studies have demonstrated an association between HTR3 variants and psychiatric and neurogastroenterologic phenotypes. Recently, their potential as predictors of nausea and vomiting and treatment of psychiatric disorders became evident. This information is now available in the serotonin receptor 3 HTR3 gene allelic variant database (www.htr3.uni-hd.de), which contains five sub-databases, one for each of the five different serotonin receptor genes HTR3A-E. Information on HTR3 variants, their functional relevance, associated phenotypes, and pharmacogenetic data such as drug response and side effects are available. This central information pool should help clinicians as well as scientists to evaluate their findings and to use the relevant information for subsequent genotype-phenotype correlation studies and pharmacogenetic approaches.
Collapse
Affiliation(s)
- Jacopo Celli
- Center of Human and Clinical Genetics, Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands
| | - Gudrun Rappold
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| | - Beate Niesler
- Department of Human Molecular Genetics, University of Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
12
|
Correia SS, Goosens KA. Input-specific contributions to valence processing in the amygdala. ACTA ACUST UNITED AC 2016; 23:534-43. [PMID: 27634144 PMCID: PMC5026206 DOI: 10.1101/lm.037887.114] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 04/26/2016] [Indexed: 10/25/2022]
Abstract
Reward and punishment are often thought of as opposing processes: rewards and the environmental cues that predict them elicit approach and consummatory behaviors, while punishments drive aversion and avoidance behaviors. This framework suggests that there may be segregated brain circuits for these valenced behaviors. The basolateral amygdala (BLA) is one brain region that contributes to both types of motivated behavior. Individual neurons in the BLA can favor positive over negative valence, or vice versa, but these neurons are intermingled, showing no anatomical segregation. The amygdala receives inputs from many brain areas and current theories posit that encoding of positive versus negative valence by BLA neurons is determined by the wiring of each neuron. Specifically, many projections from other brain areas that respond to positive and negative valence stimuli and predictive cues project strongly to the BLA and likely contribute to valence processing within the BLA. Here we review three of these areas, the basal forebrain, the dorsal raphe nucleus and the ventral tegmental area, and discuss how these may promote encoding of positive and negative valence within the BLA.
Collapse
Affiliation(s)
- Susana S Correia
- McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| | - Ki A Goosens
- McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
| |
Collapse
|
|
13
|
Kim HW, Kang JI, Lee SH, An SK, Sohn SY, Hwang EH, Lee SY, Kim SJ. Common variants of HTR3 genes are associated with obsessive-compulsive disorder and its phenotypic expression. Sci Rep 2016; 6:32564. [PMID: 27616601 PMCID: PMC5018838 DOI: 10.1038/srep32564] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/09/2016] [Indexed: 12/24/2022] Open
Abstract
Evidence from literature supports the existence of associations between serotonin-related genetic variants and obsessive-compulsive disorder (OCD), but few studies have explored the involvement of serotonin receptor type 3 genes (HTR3) in OCD. To identify whether HTR3 variability affects an individual’s susceptibility to OCD, we examined 10 HTR3 variants in 596 individuals with OCD and 599 controls. A significant difference existed in the genotypic distribution of the HTR3B variant rs1176744 between individuals with OCD and controls (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.60–0.91, P = 0.0043). A protective haplotype in HTR3B was also associated with OCD (OR = 0.77, CI = 0.63–0.95, permutated P = 0.0179). Analyses of OCD sub-phenotypes demonstrated significant associations between rs3758987 and early onset OCD in male subjects (OR = 0.49, CI = 0.31–0.79, P = 0.0031) and among rs6766410, rs6443930, and the cleaning dimension in female subjects (OR = 0.36, CI = 0.18–0.69, P = 0.0016 and OR = 0.47, CI = 0.29–0.79, P = 0.0030, respectively). Additionally, rs6766410 was related to contamination-based disgust in OCD (P = 0.0044). These results support that common HTR3 variants are involved in OCD and some of its clinical phenotypes.
Collapse
Affiliation(s)
- Hae Won Kim
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jee In Kang
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang-Hyuk Lee
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Suk Kyoon An
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Yun Sohn
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Hee Hwang
- Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Su Young Lee
- Department of Psychiatry, Cheil General Hospital &Women's Healthcare Center, Dankook University College of Medicine, Seoul, Republic of Korea
| | - Se Joo Kim
- Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea.,Institute of Behavioral Science in Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
14
|
Gupta D, Prabhakar V, Radhakrishnan M. 5HT3 receptors: Target for new antidepressant drugs. Neurosci Biobehav Rev 2016; 64:311-25. [PMID: 26976353 DOI: 10.1016/j.neubiorev.2016.03.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Revised: 02/29/2016] [Accepted: 03/01/2016] [Indexed: 12/31/2022]
Abstract
5HT3 receptors (5HT3Rs) have long been identified as a potential target for antidepressants. Several studies have reported that antagonism of 5HT3Rs produces antidepressant-like effects. However, the exact role of 5HT3Rs and the mode of antidepressant action of 5HT3R antagonists still remain a mystery. Here, we provide a comprehensive overview of 5HT3Rs: (a) regional and subcellular distribution of 5HT3Rs in discrete brain regions, (b) preclinical and clinical evidence supporting the antidepressant effect of 5HT3R antagonists, and (c) neurochemical, biological and neurocellular signaling pathways associated with the antidepressant action of 5HT3R antagonists. 5HT3Rs located on the serotonergic and other neurotransmitter interneuronal projections control their release and affect mood and emotional behavior; however, new evidence suggests that apart from modulating the neurotransmitter functions, 5HT3R antagonists have protective effects in the pathogenic events including hypothalamic-pituitary-adrenal-axis hyperactivity, brain oxidative stress and impaired neuronal plasticity, pointing to hereby unknown and novel mechanisms of their antidepressant action. Nonetheless, further investigations are warranted to establish the exact role of 5HT3Rs in depression and antidepressant action of 5HT3R antagonists.
Collapse
Affiliation(s)
- Deepali Gupta
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
| | - Visakh Prabhakar
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
| | - Mahesh Radhakrishnan
- Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India.
| |
Collapse
|
|
15
|
Gazouli M, Wouters MM, Kapur-Pojskić L, Bengtson MB, Friedman E, Nikčević G, Demetriou CA, Mulak A, Santos J, Niesler B. Lessons learned--resolving the enigma of genetic factors in IBS. Nat Rev Gastroenterol Hepatol 2016; 13:77-87. [PMID: 26726033 DOI: 10.1038/nrgastro.2015.206] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case-control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi)genetic research and provides a vision on how to address and improve (epi)genetic approaches in this complex disorder in the future.
Collapse
Affiliation(s)
- Maria Gazouli
- Department of Basic Sciences, Laboratory of Biology, School of Medicine, University of Athens, Michalakopoulou 176, 11527 Athens, Greece
| | - Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Herestraat 49, Leuven 3000, Belgium
| | - Lejla Kapur-Pojskić
- Institute for Genetic Engineering and Biotechnology, University of Sarajevo, Kemalbegova 10, 71.000 Sarajevo, Bosnia and Herzegovina
| | - May-Bente Bengtson
- Vestfold Hospital Trust, Tønsberg, Department of Internal Medicine, Division of Gastroenterology, P.O. Box 2168, 3103 Tønsberg, Norway
| | - Eitan Friedman
- The Suzanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Centre, 52621 Tel-Hashomer, Israel
| | - Gordana Nikčević
- Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 23 11010 Belgrade, Serbia
| | - Christiana A Demetriou
- Department of Electron Microscopy / Molecular Pathology, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus
| | - Agata Mulak
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland
| | - Javier Santos
- Neuro-immuno-gastroenterology Lab, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca. Department of Gastroenterology, Hospital Universitari Vall d'Hebron &Facultat de Medicina, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Paseo Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| |
Collapse
|
|
16
|
Jang KI, Lee SH, Huh HJ, Chae JH. Influence of the 5-HT3A Receptor Gene Polymorphism and Childhood Sexual Trauma on Central Serotonin Activity. PLoS One 2015; 10:e0145269. [PMID: 26701104 PMCID: PMC4689356 DOI: 10.1371/journal.pone.0145269] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 12/02/2015] [Indexed: 01/21/2023] Open
Abstract
Background Gene-environment interactions are important for understanding alterations in human brain function. The loudness dependence of auditory evoked potential (LDAEP) is known to reflect central serotonergic activity. Single nucleotide polymorphisms (SNPs) in the 5-HT3A serotonin receptor gene are associated with psychiatric disorders. This study aimed to investigate the effect between 5-HT3A receptor gene polymorphisms and childhood sexual trauma on the LDAEP as an electrophysiological marker in healthy subjects. Methods A total of 206 healthy subjects were recruited and evaluated using the childhood trauma questionnaire (CTQ) and hospital anxiety and depression scale (HADS). Peak-to-peak N1/P2 was measured at five stimulus intensities, and the LDAEP was calculated as the linear-regression slope. In addition, the rs1062613 SNPs of 5-HT3A (CC, CT, and TT) were analyzed in healthy subjects. Results There was a significant interaction between scores on the CTQ-sexual abuse subscale and 5-HT3A genotype on the LDAEP. Subjects with the CC polymorphism had a significantly higher LDEAP than T carriers in the sexually abused group. In addition, CC genotype subjects in the sexually abused group showed a significantly higher LDAEP compared with CC genotype subjects in the non-sexually abused group. Conclusions Our findings suggest that people with the CC polymorphism of the 5-HT3A gene have a greater risk of developing mental health problems if they have experienced childhood sexual abuse, possibly due to low central serotonin activity. Conversely, the T polymorphism may be protective against any central serotonergic changes following childhood sexual trauma.
Collapse
Affiliation(s)
- Kuk-In Jang
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, College of Medicine, Seoul, Korea
- Clinical Emotion and Cognition Research Laboratory, Inje University, Goyang, Korea
| | - Seung-Hwan Lee
- Department of Psychiatry, Inje University College of Medicine, Ilsan Paik Hospital, Goyang, Korea
- Clinical Emotion and Cognition Research Laboratory, Inje University, Goyang, Korea
| | - Hyu Jung Huh
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea
| | - Jeong-Ho Chae
- Department of Biomedicine & Health Sciences, The Catholic University of Korea, College of Medicine, Seoul, Korea
- Department of Psychiatry, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea
- * E-mail:
| |
Collapse
|
|
17
|
Abstract
Aggression and violence represent a significant public health concern and a clinical challenge for the mental healthcare provider. A great deal has been revealed regarding the neurobiology of violence and aggression, and an integration of this body of knowledge will ultimately serve to advance clinical diagnostics and therapeutic interventions. We will review here the latest findings regarding the neurobiology of aggression and violence. First, we will introduce the construct of aggression, with a focus on issues related to its heterogeneity, as well as the importance of refining the aggression phenotype in order to reduce pathophysiologic variability. Next we will examine the neuroanatomy of aggression and violence, focusing on regional volumes, functional studies, and interregional connectivity. Significant emphasis will be on the amygdala, as well as amygdala-frontal circuitry. Then we will turn our attention to the neurochemistry and molecular genetics of aggression and violence, examining the extensive findings on the serotonergic system, as well as the growing literature on the dopaminergic and vasopressinergic systems. We will also address the contribution of steroid hormones, namely, cortisol and testosterone. Finally, we will summarize these findings with a focus on reconciling inconsistencies and potential clinical implications; and, then we will suggest areas of focus for future directions in the field.
Collapse
|
|
18
|
Näslund J, Studer E, Pettersson R, Hagsäter M, Nilsson S, Nissbrandt H, Eriksson E. Differences in Anxiety-Like Behavior within a Batch of Wistar Rats Are Associated with Differences in Serotonergic Transmission, Enhanced by Acute SRI Administration, and Abolished By Serotonin Depletion. Int J Neuropsychopharmacol 2015; 18:pyv018. [PMID: 25716782 PMCID: PMC4571633 DOI: 10.1093/ijnp/pyv018] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The anxiety-reducing effect of long-term administration of serotonin reuptake inhibitors is usually seen only in subjects with anxiety disorders, and such patients are also abnormally inclined to experience a paradoxical anxiety-enhancing effect of acute serotonin reuptake inhibition. These unique responses to serotonin reuptake inhibitors in anxiety-prone subjects suggest, as do genetic association studies, that inter-individual differences in anxiety may be associated with differences in serotonergic transmission. METHODS The one-third of the animals within a batch of Wistar rats most inclined to spend time on open arms in the elevated plus maze were compared with the one-third most inclined to avoid them with respect to indices of brain serotonergic transmission and how their behavior was influenced by serotonin-modulating drugs. RESULTS "Anxious" rats displayed higher expression of the tryptophan hydroxylase-2 gene and higher levels of the tryptophan hydroxylase-2 protein in raphe and also higher levels of serotonin in amygdala. Supporting these differences to be important for the behavioral differences, serotonin depletion obtained by the tryptophan hydroxylase-2 inhibitor p-chlorophenylalanine eliminated them by reducing anxiety in "anxious" but not "non-anxious" rats. Acute administration of a serotonin reuptake inhibitor, paroxetine, exerted an anxiety-enhancing effect in "anxious" but not "non-anxious" rats, which was eliminated by long-term pretreatment with another serotonin reuptake inhibitor, escitalopram. CONCLUSIONS Differences in an anxiogenic impact of serotonin, which is enhanced by acute serotonin reuptake inhibitor administration, may contribute to differences in anxiety-like behavior amongst Wistar rats.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Elias Eriksson
- Department of Pharmacology, Institute of Neuroscience and Physiology at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (Dr Näslund, Mr Studer, Mr Pettersson, Drs Hagsäter, Nissbrandt, and Eriksson); Institute of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden (Dr Nilsson).
| |
Collapse
|
|
19
|
Jajodia A, Singh KD, Singhal A, Vig S, Datta M, Singh Y, Karthikeyan M, Kukreti R. Methylation of a HTR3A promoter variant alters the binding of transcription factor CTCF. RSC Adv 2015. [DOI: 10.1039/c5ra04455c] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Genetic studies pertaining to effector molecules have been pivotal in schizophrenia research.
Collapse
Affiliation(s)
- Ajay Jajodia
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | | | - Anshika Singhal
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | - Saurabh Vig
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | - Malabika Datta
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | - Yogendra Singh
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| | | | - Ritushree Kukreti
- Genomics and Molecular Medicine
- CSIR-Institute of Genomics and Integrative Biology
- Delhi-110007
- India
| |
Collapse
|
|
20
|
Nahman-Averbuch H, Yarnitsky D, Sprecher E, Granovsky Y, Granot M. Relationship between Personality Traits and Endogenous Analgesia: The Role of Harm Avoidance. Pain Pract 2014; 16:38-45. [PMID: 25353647 DOI: 10.1111/papr.12256] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 09/01/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND Whether psychological factors such as anxiety and pain catastrophizing levels influence the expression of endogenous analgesia in general and, more specifically, the conditioned pain modulation (CPM) response is still under debate. It may be assumed that other psychological characteristics also play a role in the CPM response. The neurotransmitters serotonin, dopamine, and norepinephrine are involved both in CPM, as well as personality traits such as harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), which can be obtained by the Tridimensional Personality Questionnaire (TPQ). However, the associations between these traits (HA, NS, and RD) with endogenous analgesia revealed by CPM have not yet been explored. METHODS Healthy middle-age subjects (n = 28) completed the TPQ, Spielberger's State Anxiety Inventory, and the Pain Catastrophizing Scale and were assessed for CPM paradigms using thermal phasic temporal summation as the "test stimulus" and hand immersion into hot water bath (CPM water) or contact heat (CPM contact) for "conditioning stimulus." RESULTS Higher levels of HA were associated with less-efficient CPM responses obtained by both paradigms: CPM water (r = 0.418, P = 0.027) and CPM contact (r = 0.374, P = 0.050). However, NS and RD were not associated with the other measurements. No significant relationship was observed between state anxiety and pain catastrophizing levels and the CPM responses. CONCLUSIONS The relationship between the capacity of endogenous analgesia and the tendency to avoid aversive experience can be explained by mutual mechanisms involving similar neurotransmitters or brain areas. These findings illuminate the key role of harm avoidance obtained by the TPQ in determining the characteristics of pain modulation profile.
Collapse
Affiliation(s)
- Hadas Nahman-Averbuch
- The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - David Yarnitsky
- The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.,Department of Neurology, Rambam Medical Center, Haifa, Israel
| | - Elliot Sprecher
- The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel
| | - Yelena Granovsky
- The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.,Department of Neurology, Rambam Medical Center, Haifa, Israel
| | - Michal Granot
- The Laboratory of Clinical Neurophysiology, the Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.,Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
| |
Collapse
|
|
21
|
Tsuchimine S, Taniguchi T, Sugawara N, Kaneda A, Yasui-Furukori N. No association between a polymorphism in the serotonin receptor 2B (HTR2B) gene and personality traits in healthy Japanese subjects. Neuropsychobiology 2014; 68:59-62. [PMID: 23774082 DOI: 10.1159/000350998] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Accepted: 03/24/2013] [Indexed: 11/19/2022]
Abstract
AIM The brain neurotransmitter serotonin affects many aspects of human behavior, including personality traits. Because the serotonin receptor 2B (HTR2B) gene has recently been associated with impulsivity, we investigated the potential association between the rs10194776 and Q20* polymorphism in the HTR2B gene and personality traits in healthy subjects. METHODS A total of 1,171 healthy Japanese subjects were enrolled in this study. Their personality traits were evaluated using the Temperament and Character Inventory (TCI), and the rs10194776 and Q20* genotype was determined using real-time polymerase chain reaction. RESULTS There was a significant main effect of the rs10194776 polymorphism on harm avoidance and self-directedness in females (p = 0.037 and p = 0.043, respectively). However, these differences were insignificant after a Bonferroni correction. Subjects carrying the minor allele of the Q20* polymorphism were nonexistent. CONCLUSION The results of the present study suggest that the HTR2B polymorphism is not likely to be associated with personality traits, including novelty seeking and impulsivity.
Collapse
Affiliation(s)
- Shoko Tsuchimine
- Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan
| | | | | | | | | |
Collapse
|
|
22
|
Hansson C, Alvarez-Crespo M, Taube M, Skibicka KP, Schmidt L, Karlsson-Lindahl L, Egecioglu E, Nissbrandt H, Dickson SL. Influence of ghrelin on the central serotonergic signaling system in mice. Neuropharmacology 2014; 79:498-505. [DOI: 10.1016/j.neuropharm.2013.12.012] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Revised: 11/22/2013] [Accepted: 12/14/2013] [Indexed: 02/09/2023]
|
|
23
|
Polymorphism in serotonin receptor 3B is associated with pain catastrophizing. PLoS One 2013; 8:e78889. [PMID: 24244382 PMCID: PMC3823944 DOI: 10.1371/journal.pone.0078889] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Accepted: 09/16/2013] [Indexed: 12/13/2022] Open
Abstract
Pain catastrophizing, a coping style characterized by excessively negative thoughts and emotions in relation to pain, is one of the psychological factors that most markedly predicts variability in the perception of pain; however, only little is known about the underlying neurobiology. The aim of this study was to test for associations between psychological variables, such as pain catastrophizing, anxiety and depression, and selected polymorphisms in genes related to monoaminergic neurotransmission, in particular serotonin pathway genes. Three hundred seventy-nine healthy participants completed a set of psychological questionnaires: the Pain Catastrophizing Scale (PCS), the State-Trait Anxiety Inventory and Beck’s Depression Inventory, and were genotyped for 15 single nucleotide polymorphisms (SNPs) in nine genes. The SNP rs1176744 located in the serotonin receptor 3B gene (5-HTR3B) was found to be associated with pain catastrophizing scores: both the global score and the subscales of magnification and helplessness. This is the first study to show an association between 5-HTR3B and PCS scores, thus suggesting a role of the serotonin pathway in pain catastrophizing. Since 5-HTR3B has previously been associated with descending pain modulation pathways, future studies will be of great interest to elucidate the molecular pathways involved in the relation between serotonin, its receptors and pain catastrophizing.
Collapse
|
|
24
|
Yildirim BO, Derksen JJ. Systematic review, structural analysis, and new theoretical perspectives on the role of serotonin and associated genes in the etiology of psychopathy and sociopathy. Neurosci Biobehav Rev 2013; 37:1254-96. [DOI: 10.1016/j.neubiorev.2013.04.009] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 04/09/2013] [Accepted: 04/17/2013] [Indexed: 12/18/2022]
|
|
25
|
Engel M, Smidt MP, van Hooft JA. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cell Neurosci 2013; 7:76. [PMID: 23761731 PMCID: PMC3669892 DOI: 10.3389/fncel.2013.00076] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2013] [Accepted: 05/06/2013] [Indexed: 01/28/2023] Open
Abstract
Serotonin (5-hydroxytryptamine, 5-HT), next to being an important neurotransmitter, recently gained attention as a key-regulator of pre- and postnatal development in the mammalian central nervous system (CNS). Several receptors for 5-HT are expressed in the developing brain including a ligand-gated ion channel, the 5-HT3 receptor. Over the past years, evidence has been accumulating that 5-HT3 receptors are involved in the regulation of neurodevelopment by serotonin. Here, we review the spatial and temporal expression patterns of 5-HT3 receptors in the pre- and early postnatal rodent brain and its functional implications. First, 5-HT3 receptors are expressed on GABAergic interneurons in neocortex and limbic structures derived from the caudal ganglionic eminence. Mature inhibitory GABAergic interneurons fine-tune neuronal excitability and thus are crucial for the physiological function of the brain. Second, 5-HT3 receptors are expressed on specific glutamatergic neurons, Cajal-Retzius cells in the cortex and granule cells in the cerebellum, where they regulate morphology, positioning, and connectivity of the local microcircuitry. Taken together, the 5-HT3 receptor emerges as a potential key-regulator of network formation and function in the CNS, which could have a major impact on our understanding of neurodevelopmental disorders in which 5-HT plays a role.
Collapse
Affiliation(s)
- Mareen Engel
- Center for NeuroScience, Swammerdam Institute for Life Sciences, University of AmsterdamAmsterdam, Netherlands
- Max Planck Institute of PsychiatryMunich, Germany
| | - Marten P. Smidt
- Center for NeuroScience, Swammerdam Institute for Life Sciences, University of AmsterdamAmsterdam, Netherlands
| | - Johannes A. van Hooft
- Center for NeuroScience, Swammerdam Institute for Life Sciences, University of AmsterdamAmsterdam, Netherlands
| |
Collapse
|
|
26
|
|
|
27
|
Lindahl M, Archer T. Depressive Expression and Anti-Depressive Protection in Adolescence: Stress, Positive Affect, Motivation and Self-Efficacy. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/psych.2013.46070] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
|
|
28
|
Rajkumar AP, Poonkuzhali B, Kuruvilla A, Srivastava A, Jacob M, Jacob KS. Outcome definitions and clinical predictors influence pharmacogenetic associations between HTR3A gene polymorphisms and response to clozapine in patients with schizophrenia. Psychopharmacology (Berl) 2012; 224:441-9. [PMID: 22700043 DOI: 10.1007/s00213-012-2773-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Accepted: 06/02/2012] [Indexed: 11/29/2022]
Abstract
RATIONALE Pharmacogenetics of schizophrenia has not yet delivered anticipated clinical dividends. Clinical heterogeneity of schizophrenia contributes to the poor replication of the findings of pharmacogenetic association studies. Functionally important HTR3A gene single-nucleotide polymorphisms (SNPs) were reported to be associated with response to clozapine. OBJECTIVE The aim of this study was to investigate how the association between HTR3A gene SNP and response to clozapine is influenced by various clinical predictors and by differing outcome definitions in patients with treatment-resistant schizophrenia (TRS). METHODS We recruited 101 consecutive patients with TRS, on stable doses of clozapine, and evaluated their HTR3A gene SNP (rs1062613 and rs2276302), psychopathology, and serum clozapine levels. We assessed their socio-demographic and clinical profiles, premorbid adjustment, traumatic events, cognition, and disability using standard assessment schedules. We evaluated their response to clozapine, by employing six differing outcome definitions. We employed appropriate multivariate statistics to calculate allelic and genotypic association, accounting for the effects of various clinical variables. RESULTS T allele of rs1062613 and G allele of rs2276302 were significantly associated with good clinical response to clozapine (p = 0.02). However, varying outcome definitions make these associations inconsistent. rs1062613 and rs2276302 could explain only 13.8 % variability in the responses to clozapine, while combined clinical predictors and HTR3A pharmacogenetic association model could explain 38 % variability. CONCLUSIONS We demonstrated that the results of pharmacogenetic studies in schizophrenia depend heavily on their outcome definitions and that combined clinical and pharmacogenetic models have better predictive values. Future pharmacogenetic studies should employ multiple outcome definitions and should evaluate associated clinical variables.
Collapse
Affiliation(s)
- A P Rajkumar
- Department of Psychiatry, Christian Medical College, Vellore 632002, India
| | | | | | | | | | | |
Collapse
|
|
29
|
Savli M, Bauer A, Mitterhauser M, Ding YS, Hahn A, Kroll T, Neumeister A, Haeusler D, Ungersboeck J, Henry S, Isfahani SA, Rattay F, Wadsak W, Kasper S, Lanzenberger R. Normative database of the serotonergic system in healthy subjects using multi-tracer PET. Neuroimage 2012; 63:447-59. [PMID: 22789740 DOI: 10.1016/j.neuroimage.2012.07.001] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2012] [Revised: 06/28/2012] [Accepted: 07/02/2012] [Indexed: 01/13/2023] Open
Abstract
The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0 ± 6.9 years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89 pmol/g (5-HT(1A)), 23.5 pmol/g (5-HT(1B)), 31.44 pmol/g (5-HT(2A)), and 11.33 pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders.
Collapse
Affiliation(s)
- Markus Savli
- Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Stankova T, Eichhammer P, Langguth B, Sand PG. Sexually dimorphic effects of oxytocin receptor gene (OXTR ) variants on Harm Avoidance. Biol Sex Differ 2012; 3:17. [PMID: 22846218 PMCID: PMC3472235 DOI: 10.1186/2042-6410-3-17] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 07/11/2012] [Indexed: 12/20/2022] Open
Abstract
Background Recent research has suggested that oxytocin receptor gene (OXTR) variants may account for individual differences in social behavior, the effects of stress and parenting styles. Little is known, however, on a putative role of the gene in heritable temperamental traits. Methods We addressed effects of two common OXTR variants, rs237900 and rs237902, on personality dimensions in 99 healthy subjects using the Temperament and Character Inventory. Results When sex was controlled for and an OXTR genotype*sex interaction term was included in the regression model, 11% of the variance in Harm Avoidance could be explained (uncorrected p ≤ 0.01). Female carriers of the minor alleles scored highest, and a novel A217T mutation emerged in the most harm avoidant male participant. Conclusions Findings lend support to a modulatory effect of common OXTR variants on Harm Avoidance in healthy caucasian women and invite resequencing of the gene in anxiety phenotypes to identify more explanatory functional variation.
Collapse
Affiliation(s)
- Trayana Stankova
- Department of Psychiatry and Psychotherapy, University of Regensburg, Universitaetsstrasse 84, 93053 Regensburg, Germany.
| | | | | | | |
Collapse
|
|
31
|
Watanabe N, Wada M, Irukayama-Tomobe Y, Ogata Y, Tsujino N, Suzuki M, Furutani N, Sakurai T, Yamamoto M. A single nucleotide polymorphism of the neuropeptide B/W receptor-1 gene influences the evaluation of facial expressions. PLoS One 2012; 7:e35390. [PMID: 22545105 PMCID: PMC3335863 DOI: 10.1371/journal.pone.0035390] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2011] [Accepted: 03/15/2012] [Indexed: 11/21/2022] Open
Abstract
Neuropeptide B/W receptor-1 (NPBWR1) is expressed in discrete brain regions in rodents and humans, with particularly strong expression in the limbic system, including the central nucleus of the amygdala. Recently, Nagata-Kuroiwa et al. reported that Npbwr1(-/-) mice showed changes in social behavior, suggesting that NPBWR1 plays important roles in the emotional responses of social interactions.The human NPBWR1 gene has a single nucleotide polymorphism at nucleotide 404 (404A>T; SNP rs33977775). This polymorphism results in an amino acid change, Y135F. The results of an in vitro experiment demonstrated that this change alters receptor function. We investigated the effect of this variation on emotional responses to stimuli of showing human faces with four categories of emotional expressions (anger, fear, happiness, and neutral). Subjects' emotional levels on seeing these faces were rated on scales of hedonic valence, emotional arousal, and dominance (V-A-D). A significant genotype difference was observed in valence evaluation; the 404AT group perceived facial expressions more pleasantly than did the 404AA group, regardless of the category of facial expression. Statistical analysis of each combination of [V-A-D and facial expression] also showed that the 404AT group tended to feel less submissive to an angry face than did the 404AA group. Thus, a single nucleotide polymorphism of NPBWR1 seems to affect human behavior in a social context.
Collapse
Affiliation(s)
- Noriya Watanabe
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Japan Society for the Promotion of Science, Tokyo, Japan
- Graduate School of Engineering, Tamagawa University, Machida, Tokyo, Japan
| | - Mari Wada
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Yoko Irukayama-Tomobe
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- University of Tsukuba Center for Behavioral Molecular Genetics (FIRST Program), Tokyo, Japan
| | - Yousuke Ogata
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Japan Society for the Promotion of Science, Tokyo, Japan
| | - Natsuko Tsujino
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Mika Suzuki
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Naoki Furutani
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeshi Sakurai
- Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan
- Exploratory Research for Advanced Technology Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo, Japan
| | - Miyuki Yamamoto
- Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| |
Collapse
|
|
32
|
Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsäter H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemière N, Skuse D, Poot M, Holt R, Monaco AP, Järvelä I, Kantojärvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A, Klauck SM, Poustka F, Freitag CM, Waltes R, Kopp M, Duketis E, Bacchelli E, Minopoli F, Ruta L, Battaglia A, Mazzone L, Maestrini E, Sequeira AF, Oliveira B, Vicente A, Oliveira G, Pinto D, Scherer SW, Zelenika D, Delepine M, Lathrop M, Bonneau D, Guinchat V, Devillard F, Assouline B, Mouren MC, Leboyer M, Gillberg C, Boeckers TM, Bourgeron T. Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 2012; 8:e1002521. [PMID: 22346768 PMCID: PMC3276563 DOI: 10.1371/journal.pgen.1002521] [Citation(s) in RCA: 317] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Accepted: 12/11/2011] [Indexed: 01/15/2023] Open
Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.
Collapse
Affiliation(s)
- Claire S. Leblond
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Jutta Heinrich
- Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany
| | - Richard Delorme
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France
| | | | - Catalina Betancur
- INSERM, U952, Paris, France
- CNRS, UMR 7224, Paris, France
- UPMC Univ Paris 06, Paris, France
| | - Guillaume Huguet
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Marina Konyukh
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Pauline Chaste
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Elodie Ey
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Maria Rastam
- Department of Clinical Sciences in Lund, Lund University, Lund, Sweden
| | | | - Gudrun Nygren
- Gillberg Neuropsychiatry Centre, University of Gothenburg, Göteborg, Sweden
| | - I. Carina Gillberg
- Gillberg Neuropsychiatry Centre, University of Gothenburg, Göteborg, Sweden
| | - Jonas Melke
- Institute of Neuroscience and Physiology, Department of Pharmacology, Gothenburg University, Göteborg, Sweden
| | - Roberto Toro
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Beatrice Regnault
- Eukaryote Genotyping Platform, Genopole, Institut Pasteur, Paris, France
| | - Fabien Fauchereau
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Oriane Mercati
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - Nathalie Lemière
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| | - David Skuse
- Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, London, United Kingdom
| | - Martin Poot
- Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Richard Holt
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Anthony P. Monaco
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| | - Irma Järvelä
- Department of Medical Genetics, University of Helsinki, Helsinki, Finland
| | - Katri Kantojärvi
- Department of Medical Genetics, University of Helsinki, Helsinki, Finland
| | - Raija Vanhala
- Department of Medical Genetics, University of Helsinki, Helsinki, Finland
| | - Sarah Curran
- Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, London, United Kingdom
| | - David A. Collier
- Social Genetic Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom
| | - Patrick Bolton
- Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, King's College London, London, United Kingdom
- Social Genetic Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, United Kingdom
| | - Andreas Chiocchetti
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sabine M. Klauck
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Fritz Poustka
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany
| | - Christine M. Freitag
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany
| | - Regina Waltes
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany
| | - Marnie Kopp
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany
| | - Eftichia Duketis
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany
| | - Elena Bacchelli
- Department of Biology, University of Bologna, Bologna, Italy
| | | | - Liliana Ruta
- Division of Child Neurology and Psychiatry, Department of Paediatrics, University of Catania, Catania, Italy
| | - Agatino Battaglia
- Stella Maris Clinical Research Institute for Child and Adolescent Neuropsychiatry, Pisa, Italy
| | - Luigi Mazzone
- Division of Child Neurology and Psychiatry, Department of Pediatrics, University of Catania, Catania, Italy
| | - Elena Maestrini
- Department of Biology, University of Bologna, Bologna, Italy
| | - Ana F. Sequeira
- Instituto Nacional de Saude Dr Ricardo Jorge, Lisbon, Portugal
- Instituto Gulbenkian de Ciencia, Oeiras, Portugal
- Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal
| | - Barbara Oliveira
- Instituto Nacional de Saude Dr Ricardo Jorge, Lisbon, Portugal
- Instituto Gulbenkian de Ciencia, Oeiras, Portugal
- Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal
| | - Astrid Vicente
- Instituto Nacional de Saude Dr Ricardo Jorge, Lisbon, Portugal
- Instituto Gulbenkian de Ciencia, Oeiras, Portugal
- Center for Biodiversity, Functional and Integrative Genomics, Faculdade de Ciências da Universidade de Lisboa, Lisboa, Portugal
| | - Guiomar Oliveira
- Unidade Neurodesenvolvimento e Autismo, Centro Investigação e Formação Clinica, Hospital Pediátrico Coimbra e Faculdade Medicina, Universidade Coimbra, Coimbra, Portugal
| | - Dalila Pinto
- The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Canada
| | - Stephen W. Scherer
- The Centre for Applied Genomics and Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Canada
| | | | | | | | - Dominique Bonneau
- INSERM U771 and CNRS 6214, Angers, France
- Département de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France
| | - Vincent Guinchat
- CADIPA–Centre de Ressources Autisme Rhône-Alpes, Saint Egrève, France
| | | | | | - Marie-Christine Mouren
- Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Department of Child and Adolescent Psychiatry, Paris, France
| | - Marion Leboyer
- INSERM, U955, Psychiatrie Génétique, Créteil, France
- Université Paris Est, Faculté de Médecine, Créteil, France
- AP-HP, Hôpital H. Mondor–A. Chenevier, Département de Psychiatrie, Créteil, France
| | - Christopher Gillberg
- Gillberg Neuropsychiatry Centre, University of Gothenburg, Göteborg, Sweden
- Institute of Child Health, University College London, London, United Kingdom
| | | | - Thomas Bourgeron
- Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France
- CNRS URA 2182 “Genes, synapses and cognition,” Institut Pasteur, Paris, France
- University Denis Diderot Paris 7, Paris, France
| |
Collapse
|
|
33
|
The effects of allostatic load on neural systems subserving motivation, mood regulation, and social affiliation. Dev Psychopathol 2011; 23:975-99. [PMID: 22018077 DOI: 10.1017/s0954579411000459] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AbstractThe term allostasis, which is defined as stability through change, has been invoked repeatedly by developmental psychopathologists to describe long-lasting and in some cases permanent functional alterations in limbic–hypothalamic–pituitary–adrenal axis responding following recurrent and/or prolonged exposure to stress. Increasingly, allostatic load models have also been invoked to describe psychological sequelae of abuse, neglect, and other forms of maltreatment. In contrast, neural adaptations to stress, including those incurred by monoamine systems implicated in (a) mood and emotion regulation, (b) behavioral approach, and (c) social affiliation and attachment, are usually not included in models of allostasis. Rather, structural and functional alterations in these systems, which are exquisitely sensitive to prolonged stress exposure, are usually explained as stress mediators, neural plasticity, and/or programming effects. Considering these mechanisms as distinct from allostasis is somewhat artificial given overlapping functions and intricate coregulation of monoamines and the limbic–hypothalamic–pituitary–adrenal axis. It also fractionates literatures that should be mutually informative. In this article, we describe structural and functional alterations in serotonergic, dopaminergic, and noradrenergic neural systems following both acute and prolonged exposure to stress. Through increases in behavioral impulsivity, trait anxiety, mood and emotion dysregulation, and asociality, alterations in monoamine functioning have profound effects on personality, attachment relationships, and the emergence of psychopathology.
Collapse
|
|
34
|
Mujakovic S, ter Linde JJ, de Wit NJ, van Marrewijk CJ, Fransen GA, Onland-Moret NC, Laheij RJ, Muris JW, Grobbee DE, Samsom M, Jansen JB, Knottnerus A, Numans ME. Serotonin receptor 3A polymorphism c.-42C > T is associated with severe dyspepsia. BMC MEDICAL GENETICS 2011; 12:140. [PMID: 22014438 PMCID: PMC3213216 DOI: 10.1186/1471-2350-12-140] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/10/2011] [Accepted: 10/20/2011] [Indexed: 12/16/2022]
Abstract
BACKGROUND The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT3 receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT3 receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity. METHODS Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia. RESULTS HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90). CONCLUSIONS The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT3 mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.
Collapse
Affiliation(s)
- Suhreta Mujakovic
- University Medical Centre Utrecht, Department of Gastroenterology & Hepatology, the Netherlands
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Kilpatrick LA, Labus JS, Coveleskie K, Hammer C, Rappold G, Tillisch K, Bueller JA, Suyenobu B, Jarcho JM, McRoberts JA, Niesler B, Mayer EA. The HTR3A polymorphism c. -42C>T is associated with amygdala responsiveness in patients with irritable bowel syndrome. Gastroenterology 2011; 140:1943-51. [PMID: 21420406 PMCID: PMC3757951 DOI: 10.1053/j.gastro.2011.03.011] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Revised: 02/02/2011] [Accepted: 03/07/2011] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIMS 5-Hydroxytryptamine (5-HT)3 receptor (5-HT3R) antagonists are effective in treating patients with irritable bowel syndrome (IBS) and have anxiolytic effects. Their therapeutic effects are related, in part, to reducing amygdala engagement during expected visceral pain. A single nucleotide polymorphism in HTR3A, c.-42C>T;(C178T; rs1062613), is associated with altered reactivity of the amygdala during emotional face processing in healthy subjects (controls). We evaluated the influence of this single nucleotide polymorphism on amygdala reactivity to emotional faces and nonemotional stimuli in female patients with IBS and controls. METHODS We measured brain responses during an affect-matching paradigm in 54 women (26 with IBS, 29 controls) using functional magnetic resonance imaging. We examined associations between HTR3A c.-42C>T genotype (C/C vs T carrier) and responses in amygdala and other regions of brain that expressed high levels of 5-HT3R. RESULTS The C/C genotype was associated with greater anxiety symptoms in patients with IBS and controls and increased activation of the amygdala under emotional and nonemotional conditions. Among patients with IBS, C/C genotype was associated with greater symptom ratings. A subset of IBS patients with the C/C genotype had increased amygdala responses to nonemotional stimuli, compared with other subjects with C/C genotype. CONCLUSIONS Regardless of diagnosis, the C/C genotype of the c.-42C>T polymorphism in HTR3A, compared with T carrier status, is associated with increased anxiety and amygdala responsiveness during emotional and nonemotional tasks. This polymorphism was associated with severity of IBS symptoms. Although this genotype is not sufficient for diagnosis of IBS, it is associated with severity of symptoms.
Collapse
Affiliation(s)
- Lisa A Kilpatrick
- Center for Neurobiology of Stress, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Niesler B. 5-HT(3) receptors: potential of individual isoforms for personalised therapy. Curr Opin Pharmacol 2011; 11:81-6. [PMID: 21345729 DOI: 10.1016/j.coph.2011.01.011] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Revised: 01/29/2011] [Accepted: 01/31/2011] [Indexed: 01/28/2023]
Abstract
Serotonin type 3 (5-HT(3)) receptors are ligand-gated ion channels built by five subunits of diverse composition. In humans, five subunits exist (5-HT3A-E) which are encoded by the genes HTR3A-E and are expressed in various isoforms. Recently, the importance of factors influencing receptor expression became clear, such as chaperones and microRNAs. Owing to their expression profile and physiological functions, 5-HT(3) receptors have been implicated in irritable bowel syndrome (IBS) and psychiatric disorders. Interestingly, HTR3 variants have now been shown to be associated with these conditions. This underlines the potential of 5-HT(3) receptors as therapeutic targets and may enable personalised therapies in the future.
Collapse
Affiliation(s)
- Beate Niesler
- Institute of Human Genetics, Department of Human Molecular Genetics, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
| |
Collapse
|
|
37
|
Gatt JM, Williams LM, Schofield PR, Dobson-Stone C, Paul RH, Grieve SM, Clark CR, Gordon E, Nemeroff CB. Impact of the HTR3A gene with early life trauma on emotional brain networks and depressed mood. Depress Anxiety 2010; 27:752-9. [PMID: 20694966 DOI: 10.1002/da.20726] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The risk for mental illnesses such as depression is increasingly conceptualized as the product of gene-environment interactions and their impact on brain structure and function. The role of serotonin 3A receptor gene (HTR3A -42C>T polymorphism) and its interaction with early life stress (ELS) was investigated in view of the receptor's localization to brain regions central to emotion processing. METHODS Fronto-limbic grey matter (GM) loss was measured using magnetic resonance imaging and assessed using voxel-based morphometry analysis in 397 nonclinical individuals from the Brain Resource International Database. Negative mood symptoms were also assessed. RESULTS The HTR3A CC genotype group, compared to the T carriers, demonstrated comparative loss to GM in hippocampal structures, which extended to the frontal cortices for those CC genotype individuals also exposed to ELS. Elevations in depressed mood were also evident. CONCLUSIONS These findings suggest that the HTR3A CC genotype may be associated with alterations in brain structures central to emotion processing, particularly when exposed to stress, and further highlight the potential role of the serotonin system in the pathophysiology of affective disorders. In contrast, those individuals with the T allele, in particular the TT genotype, may be more protected from such alterations combined with minimal exposure to ELS events.
Collapse
Affiliation(s)
- Justine M Gatt
- The Brain Dynamics Center, Westmead Millennium Institute & Discipline of Psychiatry, University of Sydney at Westmead Hospital, New South Wales, Australia
| | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Walstab J, Rappold G, Niesler B. 5-HT(3) receptors: role in disease and target of drugs. Pharmacol Ther 2010; 128:146-69. [PMID: 20621123 DOI: 10.1016/j.pharmthera.2010.07.001] [Citation(s) in RCA: 158] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2010] [Accepted: 06/21/2010] [Indexed: 12/19/2022]
Abstract
Serotonin type 3 (5-HT(3)) receptors are pentameric ion channels belonging to the superfamily of Cys-loop receptors. Receptor activation either leads to fast excitatory responses or modulation of neurotransmitter release depending on their neuronal localisation. 5-HT(3) receptors are known to be expressed in the central nervous system in regions involved in the vomiting reflex, processing of pain, the reward system, cognition and anxiety control. In the periphery they are present on a variety of neurons and immune cells. 5-HT(3) receptors are known to be involved in emesis, pain disorders, drug addiction, psychiatric and GI disorders. Progress in molecular genetics gives direction to personalised medical strategies for treating complex diseases such as psychiatric and functional GI disorders and unravelling individual drug responses in pharmacogenetic approaches. Here we discuss the molecular basis of 5-HT(3) receptor diversity at the DNA and protein level, of which our knowledge has greatly extended in the last decade. We also evaluate their role in health and disease and describe specific case-control studies addressing the involvement of polymorphisms of 5-HT3 subunit genes in complex disorders and responses to drugs. Furthermore, we focus on the actual state of the pharmacological knowledge concerning not only classical 5-HT(3) antagonists--the setrons--but also compounds of various substance classes targeting 5-HT(3) receptors such as anaesthetics, opioids, cannabinoids, steroids, antidepressants and antipsychotics as well as natural compounds derived from plants. This shall point to alternative treatment options modulating the 5-HT(3) receptor system and open new possibilities for drug development in the future.
Collapse
Affiliation(s)
- Jutta Walstab
- Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | | | | |
Collapse
|
|
39
|
Functional variants of the serotonin receptor type 3A and B gene are associated with eating disorders. Pharmacogenet Genomics 2009; 19:790-9. [PMID: 19741568 DOI: 10.1097/fpc.0b013e32833132b3] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVE As a key player in modulating both human physiological and behavioural functions including anxiety, perception and in particular appetite, serotonin (5-hydroxytryptamine, 5-HT) is likely to be involved in the aetiology of eating disorders. Studies showing serotonin receptor type 3 (5-HT3) receptors to mediate food intake depression (anorexic response) have triggered our interest in investigating the putative role of variants in the 5-HT3 receptor genes, HTR3A and HTR3B, in the susceptibility to anorexia nervosa (AN) and bulimia nervosa (BN). METHODS Two hundred and sixty-five patients with AN and 91 patients with BN as well as 191 healthy controls served as a pilot study group for mutational analysis by direct sequencing. Variants showing a significant association were subsequently genotyped in an independent Spanish cohort of 78 patients with AN and 119 patients with BN as well as 331 healthy controls for replication purposes. RESULTS In the pilot study, we found the coding HTR3B variant, p.Y129S, (rs1176744, P = 0.004, odds ratio = 2.06) to be associated with the restrictive subtype of AN. The association was confirmed in the Spanish study group (P = 0.034, odds ratio = 2.26). CONCLUSION Our study provides first evidence for an involvement of 5-HT3 variants in the aetiopathology of eating disorders in humans.
Collapse
|
|
40
|
Tang TZ, DeRubeis RJ, Hollon SD, Amsterdam J, Shelton R, Schalet B. Personality change during depression treatment: a placebo-controlled trial. ACTA ACUST UNITED AC 2009; 66:1322-30. [PMID: 19996037 DOI: 10.1001/archgenpsychiatry.2009.166] [Citation(s) in RCA: 214] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
CONTEXT High neuroticism is a personality risk factor that reflects much of the genetic vulnerability to major depressive disorder (MDD), and low extraversion may increase risk as well. Both have been linked to the serotonin system. OBJECTIVES To test whether patients with MDD taking selective serotonin reuptake inhibitors (SSRIs) report greater changes in neuroticism and extraversion than patients receiving inert placebo, and to examine the state effect hypothesis that self-reported personality change during SSRI treatment is merely a change of depression-related measurement bias. DESIGN A placebo-controlled trial. SETTING Research clinics. Patients Adult patients with moderate to severe MDD randomized to receive paroxetine (n = 120), placebo (n = 60), or cognitive therapy (n = 60). OUTCOME MEASURES NEO Five-Factor Inventory and Hamilton Rating Scale for Depression. RESULTS Patients who took paroxetine reported greater personality change than placebo patients, even after controlling for depression improvement (neuroticism, P < .001; extraversion, P = .002). The advantage of paroxetine over placebo in antidepressant efficacy was no longer significant after controlling for change in neuroticism (P = .46) or extraversion (P = .14). Patients taking paroxetine reported 6.8 times as much change on neuroticism and 3.5 times as much change on extraversion as placebo patients matched for depression improvement. Although placebo patients exhibited substantial depression improvement (Hamilton Rating Scale for Depression score, -1.2 SD, P < .001), they reported little change on neuroticism (-0.18 SD, P = .08) or extraversion (0.08 SD, P = .50). Cognitive therapy produced greater personality change than placebo (P </= .01); but its advantage on neuroticism was no longer significant after controlling for depression (P = .14). Neuroticism reduction during treatment predicted lower relapse rates among paroxetine responders (P = .003) but not among cognitive therapy responders (P = .86). CONCLUSIONS Paroxetine appears to have a specific pharmacological effect on personality that is distinct from its effect on depression. If replicated, this pattern would disconfirm the state effect hypothesis and instead support the notion that SSRIs' effects on personality go beyond and perhaps contribute to their antidepressant effects.
Collapse
Affiliation(s)
- Tony Z Tang
- Northwestern University, Evanston, IL 60208, USA.
| | | | | | | | | | | |
Collapse
|
|
41
|
Anderson BM, Schnetz-Boutaud NC, Bartlett J, Wotawa AM, Wright HH, Abramson RK, Cuccaro ML, Gilbert JR, Pericak-Vance MA, Haines JL. Examination of association of genes in the serotonin system to autism. Neurogenetics 2009; 10:209-16. [PMID: 19184136 PMCID: PMC2753863 DOI: 10.1007/s10048-009-0171-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Accepted: 01/05/2009] [Indexed: 01/31/2023]
Abstract
Autism is characterized as one of the pervasive developmental disorders, a spectrum of often severe behavioral and cognitive disturbances of early development. The high heritability of autism has driven multiple efforts to identify genetic variation that increases autism susceptibility. Numerous studies have suggested that variation in peripheral and central metabolism of serotonin (5-hydroxytryptamine) may play a role in the pathophysiology of autism. We screened 403 autism families for 45 single nucleotide polymorphisms in ten serotonin pathway candidate genes. Although genome-wide linkage scans in autism have provided support for linkage to various loci located within the serotonin pathway, our study does not provide strong evidence for linkage to any specific gene within the pathway. The most significant association (p = 0.0002; p = 0.02 after correcting for multiple comparisons) was found at rs1150220 (HTR3A) located on chromosome 11 ( approximately 113 Mb). To test specifically for multilocus effects, multifactor dimensionality reduction was employed, and a significant two-way interaction (p value = 0.01) was found between rs10830962, near MTNR1B (chromosome11; 92,338,075 bp), and rs1007631, near SLC7A5 (chromosome16; 86,413,596 bp). These data suggest that variation within genes on the serotonin pathway, particularly HTR3A, may have modest effects on autism risk.
Collapse
Affiliation(s)
- B M Anderson
- Center for Human Genetics Research, Vanderbilt University Medical Center, 519 Light Hall, Nashville, TN 37232-0700, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
3B but which 3B and that's just one of the questions: the heterogeneity of human 5-HT3 receptors. Trends Pharmacol Sci 2009; 29:437-44. [PMID: 18597859 DOI: 10.1016/j.tips.2008.06.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Revised: 04/14/2008] [Accepted: 06/15/2008] [Indexed: 01/19/2023]
Abstract
The 5-hydroxytryptamine 3 (5-HT3) receptor is expressed widely in the central and peripheral nervous systems, where it mediates or modulates a wide range of physiological processes. The receptor is targeted by drugs administered for nausea and/or emesis and irritable bowel syndrome and has been proposed as a potential drug target in various psychiatric disorders. The 5-HT3 receptor is a pentameric ligand-gated ion channel and belongs to the Cys-loop receptor family. In contrast to the immense heterogeneity characterizing other Cysloop receptors, native 5-HT3 receptors historically have been considered a much more homogenous receptor population. However, the recent discovery of additional 5-HT3 subunits and the dawning realization that central and peripheral 5-HT3 receptor populations might comprise several subtypes characterized by distinct functional properties has emphasized the complexity of human 5-HT3 receptor signaling. In this review potential implications of these findings and of the entirely new layer of interindividual diversity introduced to the 5-HT3 receptor system by genetic variations will be outlined.
Collapse
|
|
43
|
Kapeller J, Houghton LA, Mönnikes H, Walstab J, Möller D, Bönisch H, Burwinkel B, Autschbach F, Funke B, Lasitschka F, Gassler N, Fischer C, Whorwell PJ, Atkinson W, Fell C, Büchner KJ, Schmidtmann M, van der Voort I, Wisser AS, Berg T, Rappold G, Niesler B. First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum Mol Genet 2008; 17:2967-2977. [PMID: 18614545 DOI: 10.1093/hmg/ddn195] [Citation(s) in RCA: 148] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Diarrhea predominant irritable bowel syndrome (IBS-D) is a complex disorder related to dysfunctions in the serotonergic system. As cis-regulatory variants can play a role in the etiology of complex conditions, we investigated the untranslated regions (UTRs) of the serotonin receptor type 3 subunit genes HTR3A and HTR3E. Mutation analysis was carried out in a pilot sample of 200 IBS patients and 100 healthy controls from the UK. The novel HTR3E 3'-UTR variant c.*76G>A (rs62625044) was associated with female IBS-D (P = 0.033, OR = 8.53). This association was confirmed in a replication study, including 119 IBS-D patients and 195 controls from Germany (P = 0.0046, OR = 4.92). Pooled analysis resulted in a highly significant association of c.*76G>A with female IBS-D (P = 0.0002, OR = 5.39). In a reporter assay, c.*76G>A affected binding of miR-510 to the HTR3E 3'-UTR and caused elevated luciferase expression. HTR3E and miR-510 co-localize in enterocytes of the gut epithelium as shown by in situ hybridization and RT-PCR. This is the first example indicating micro RNA-related expression regulation of a serotonin receptor gene with a cis-regulatory variant affecting this regulation and appearing to be associated with female IBS-D.
Collapse
Affiliation(s)
- Johannes Kapeller
- Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Holmes A. Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease. Neurosci Biobehav Rev 2008; 32:1293-314. [PMID: 18439676 PMCID: PMC2561331 DOI: 10.1016/j.neubiorev.2008.03.006] [Citation(s) in RCA: 206] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2007] [Accepted: 02/20/2008] [Indexed: 01/09/2023]
Abstract
The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.
Collapse
Affiliation(s)
- Andrew Holmes
- Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, NIH, 5625 Fishers Lane Room 2N09, Rockville, MD 20852-9411, USA.
| |
Collapse
|
|
45
|
Abstract
There is accumulating evidence of a genetic predisposition for developing a functional gastrointestinal (GI) disorder. Identification of the genetic factors may improve understanding of underlying pathophysiological mechanisms. We aimed to test the association of functional polymorphisms in genes involved in serotonergic signalling and G-protein-mediated signal transduction, both affecting gastroduodenal sensory and motor function, with functional dyspepsia (FD). FD patients, send to our tertiary referral centre, were studied (n = 112). Healthy controls (n = 336) free of GI symptoms were matched 1 : 3 for age and gender. Polymorphisms in genes encoding the serotonin receptor type three A subunit (HTR3A), the serotonin transporter (SERT) and the G-protein beta3 subunit (GNB3) were analysed. The FD patients displayed a higher prevalence of the T allele of the GNB3 C825T polymorphism compared to healthy controls (OR = 1.60, 95% CI: 1.03-2.49, P = 0.038). No association between FD and the genotype of the insertion/deletion polymorphism in the promoter of SERT (SERT-P) or HTR3A C178T polymorphism was observed. Tertiary referral FD is associated with the 825T allele of the GNB3 gene. The increased signal transduction associated with this allele may contribute to the abnormalities in gastroduodenal sensory and motor function observed in FD.
Collapse
Affiliation(s)
- N van Lelyveld
- Gastrointestinal Research Unit, Department of Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands.
| | | | | | | |
Collapse
|
|
46
|
Serotonin receptor 3A (HTR3A) gene is associated with personality traits, but not panic disorder. Psychiatr Genet 2008; 18:44. [PMID: 18197086 DOI: 10.1097/ypg.0b013e3282f02099] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
47
|
Niesler B, Kapeller J, Hammer C, Rappold G. Serotonin type 3 receptor genes: HTR3A, B, C, D, E. Pharmacogenomics 2008; 9:501-4. [DOI: 10.2217/14622416.9.5.501] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
The 5-HT3 receptor is a ligand-gated ion channel composed of five subunits. To date, five different human subunits are known, 5-HT3A–E, which are encoded by the serotonin receptor genes HTR3A, HTR3B, HTR3C, HTR3D and HTR3E, respectively. Functional receptors are pentameric complexes of diverse composition. Different receptor subtypes seem to be involved in chemotherapy-induced nausea and vomiting (CINV), irritable bowel syndrome and psychiatric disorders. 5-HT3 receptor antagonists are established in the therapy of CINV and irritable bowel syndrome. HTR3A and HTR3B polymorphisms may also contribute to the etiology of psychiatric disorders and serve as predictors in CINV and in the medical treatment of psychiatric patients.
Collapse
Affiliation(s)
- Beate Niesler
- Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Johannes Kapeller
- Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Christian Hammer
- Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| | - Gudrun Rappold
- Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany
| |
Collapse
|
|
48
|
Xiong W, Hosoi M, Koo BN, Zhang L. Anandamide inhibition of 5-HT3A receptors varies with receptor density and desensitization. Mol Pharmacol 2008; 73:314-22. [PMID: 17993512 DOI: 10.1124/mol.107.039149] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2025] Open
Abstract
Converging evidence has suggested that anandamide (AEA), an endogenous agonist of cannabinoid (CB) receptors, can directly interact with certain types of ligand-gated ion channels (LGICs). However, little is known about the molecular and cellular mechanisms of AEA-induced direct effects on LGICs. Here, we report that AEA inhibited the function of serotoningated ion channels (5-HT(3A)) expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells in a manner that was dependent on the steady-state receptor density at the cell surface. The magnitude of AEA inhibition was inversely correlated with the expression levels of receptor protein and function. With increasing surface receptor expression, the magnitude of AEA inhibition decreased. Consistent with this idea, pretreatment with actinomycin D, which inhibits transcription, decreased the amplitude of current activated by maximal concentrations of 5-hydroxytryptamine (5-HT) and increased the magnitude of AEA inhibition. AEA did not significantly alter 5-HT(3A) receptor trafficking. However, AEA accelerated 5-HT(3A) receptor desensitization time in a concentration-dependent manner without significantly changing receptor activation and deactivation time. The desensitization time was correlated with the AEA-induced inhibiting effect and mean 5-HT current density. Applications of 5-hydroxyindole and nocodazole, a microtubule disruptor, significantly slowed 5-HT(3A) receptor desensitization and reduced the magnitude of AEA inhibition. These observations suggest that 5-HT(3) receptor density at the steady state regulates receptor desensitization kinetics and the potency of AEA-induced inhibiting effect on the receptors. The inhibition of 5-HT(3) receptors by AEA may contribute to its physiological roles in control of pain and emesis.
Collapse
Affiliation(s)
- Wei Xiong
- Laboratory for Integrative Neuroscience National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892, USA.
| | | | | | | |
Collapse
|
|
49
|
Frazzetto G, Gross C. Beyond susceptibility. Behavioural genetics can advance our understanding of psychiatric disorders, but might not meet the expectations for new cures. EMBO Rep 2007; 8 Spec No:S3-6. [PMID: 17726439 PMCID: PMC3327531 DOI: 10.1038/sj.embor.7401013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Giovanni Frazzetto
- European Molecular Biology Laboratory Monterotondo, Italy. BIOS Centre, London School of Economics, London, UK.E-mail:
| | - Cornelius Gross
- European Molecular Biology Laboratory Monterotondo, Italy. BIOS Centre, London School of Economics, London, UK.E-mail:
| |
Collapse
|
|
50
|
Krzywkowski K. Do polymorphisms in the human 5-HT3 genes contribute to pathological phenotypes? Biochem Soc Trans 2007; 34:872-6. [PMID: 17052218 DOI: 10.1042/bst0340872] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
5-HT3 receptors are members of the Cys-loop superfamily of ligand-gated ion channels. In both the central and the peripheral nervous systems, 5-HT3 receptors excite postsynaptic cells and modulate the release of neurotransmitters from presynaptic neurons. 5-HT3 receptors are known to be involved in mediation of nausea/emesis caused by chemo/radio-therapy and anaesthesia, and more recently have also been found to be involved in irritable bowel syndrome. 5-HT3 receptors have also been suggested to play a role in a range of other indications, including various psychiatric disorders. This review summarizes the current evidence for the contribution of 5-HT3 subunit genes to disease phenotypes arising from association studies. Furthermore, it suggests how in vitro characterization of naturally occurring genetic variants can be used to obtain a better understanding of the causal relationship between gene and disease.
Collapse
Affiliation(s)
- K Krzywkowski
- Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
| |
Collapse
|