BioProject

The aim of the study was to evaluate cocaine-induced changes in gene expression in a dopaminergic model. More...

The aim of the study was to evaluate cocaine-induced changes in gene expression in a dopaminergic model. Cocaine reward and reinforcing effects are mediated mainly by dopaminergic neurotransmission. In this study we aimed at evaluating gene expression changes induced by acute cocaine exposure on SH-SY5Y differentiated cells, which have been widely used as a dopaminergic neuronal model. Expression changes and a concomitant increase in neuronal activity were observed 6 hours after a 5 uM cocaine exposure, whereas no changes in gene expression nor in neuronal activity took place at 1 uM cocaine. A total of 756 differentially expressed genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as MAPK, CREB, neurotrophin and neuregulin signaling pathways. Genes displaying altered expression were subsequently targeted with predicted functional SNPs in a case-control association study in a sample of 806 cocaine-dependent patients and 817 controls. This study highlighted associations between cocaine dependence and five SNPs predicted to alter microRNA binding at the 3’UTR of the NFAT5 gene. The association of SNP rs1437134 with cocaine dependence survived the Bonferroni correction for multiple testing. A functional effect was confirmed for this variant by a luciferase reporter assay, with lower expression observed for the rs1437134G allele, which was more pronounced in the presence of hsa-miR-509. However, brain volumes in regions of relevance to addiction, as assessed with MRI, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is up-regulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence. Overall design: for each condition, 9 dishes containing SH-SY5Y were used. Pools of RNA from three dishes were used for each replicate in the microarray. Less...