Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies |
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| Authors: | Sergi Mas Patricia Gassó Miquel Bernardo Amalia Lafuente |
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| Affiliation: | 1. Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Casanova 143, E-08036 Barcelona, Spain;2. Psychiatry Service, Hospital Clinic de Barcelona, Villarroel 170, E-08036 Barcelona, Spain;3. Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Casanova 143, E-08036 Barcelona, Spain;4. Institut d''Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;5. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain;1. Beijing Neurosurgical Institute, Beijing 100050, China;2. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China;3. Chinese Glioma Cooperative Group (CGCG), China;4. Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China;5. Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China;1. Institute of Anatomy and Cell Biology, Universitätsmedizin Greifswald, Friedrich Löffler Straße 23c, 17487 Greifswald, Germany;2. Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland;3. Department of Pediatric Surgery, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany;4. Department of Obstetrics, Centre for Fetal Medicine, Division of Women and Child Health, University of Leipzig, Leipzig, Germany;1. University of Natural Resources and Life Sciences, Vienna, Department of Crop Sciences, Division of Agronomy, Konrad Lorenz Str. 24, 3430 Tulln, Austria;2. University of Natural Resources and Life Sciences, Vienna, Department of Crop Sciences, Division of Plant Breeding, Konrad Lorenz Str. 24, 3430 Tulln, Austria;3. University of Natural Resources and Life Sciences, Vienna, Department of Water, Atmosphere and Environment, Institute of Meteorology, Peter-Jordan-Str. 82, 1190 Vienna, Austria;4. University of Natural Resources and Life Sciences, Vienna, Department of Forest and Soil Sciences, Institute of Soil Research, Konrad Lorenz Str. 24, 3430 Tulln, Austria;1. Laboratory of Pharmacogenomics, Section of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy;2. McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada;3. Unit of Clinical Pharmacology, University Hospital of Cagliari, Cagliari, Italy;4. Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada;5. Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada;6. University of Patras School of Health Sciences, Department of Pharmacy, University Campus, Rion, Patras, Greece;1. Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Vic. 3010, Australia;2. Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Vic. 3010, Australia;3. Centre for Neuroscience Research, University of Melbourne, Melbourne, Vic. 3010, Australia |
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| Abstract: | Risperidone is a potent antagonist of both dopamine and serotonin receptors. However, little is known about the underlying molecular mechanism by which risperidone acts. Although a number of genetic variants have been observed to correlate with treatment response there are no definitive predictors of response. We performed a genome-wide gene expression analysis (Human Genome U219 Array Plate) of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. Our results revealed that cellular risperidone treatment is associated with a range of gene expression changes, which are time (6–48 h) and dose related (0.1–10 μM). We found that functional clusters of these changes correspond to Gene Ontology categories related to neural cell development functions, and synaptic structure and functions. We also identified Canonical Pathways related to these functional categories: neurogenesis and axon guidance; synaptic vesicle; and neurotransmitter signaling (dopamine, serotonin and glutamate). Finally, we identified candidate genes for pharmacogenetic studies related to the main risperidone secondary effects: motor disorders, cardiovascular disorders and metabolic disorders. Our results suggest that risperidone treatment affects the neurogenesis and neurotransmission of neuroblastoma cells, which is in agreement with the “initiation and adaptation” model to explain the mechanism of action of psychotropic drugs. |
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