Functional analysis of gene expression in risperidone treated cells provide new insights in molecular mechanism and new candidate genes for pharmacogenetic studies

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 pre...

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Bibliographic Details
Published in:European neuropsychopharmacology 2013-04, Vol.23 (4), p.329-337
Main Authors: Mas, Sergi, Gassó, Patricia, Bernardo, Miquel, Lafuente, Amalia
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Dopamine
Gene expression
Gene Expression Regulation, Neoplastic
Genetic Association Studies - methods
Glutamate
Humans
Internal Medicine
Neurogenesis
Neurogenesis - drug effects
Neurogenesis - physiology
Pharmacogenetics - methods
Psychiatry
Risperidone
Risperidone - pharmacology
Serotonin
Synaptic plasticity
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Summary: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.
ISSN:0924-977X
1873-7862
DOI:10.1016/j.euroneuro.2012.04.016