Abstract

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 after a 5 μM cocaine exposure, whereas no changes in gene expression or in neuronal activity took place at 1 μM cocaine. Changes in gene expression were identified in a total of 756 genes, mainly related to regulation of transcription and gene expression, cell cycle, adhesion and cell projection, as well as mitogen-activeated protein kinase (MAPK), CREB, neurotrophin and neuregulin signaling pathways. Some genes displaying altered expression were subsequently targeted with predicted functional single-nucleotide polymorphisms (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′-untranslated region 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 magnetic resonance imaging, did not correlate with NFAT5 variation. These results suggest that the NFAT5 gene, which is upregulated a few hours after cocaine exposure, may be involved in the genetic predisposition to cocaine dependence.

Highlights

  • Cocaine is a psychostimulant drug of abuse and its use has become a public health problem worldwide

  • Under the hypothesis that cocaine-induced gene expression changes may highlight novel candidate genes predisposing to cocaine dependence, we performed an in vitro study in a dopaminergic neuron-like model to assess transcriptional changes induced by cocaine

  • Cocaine-induced changes in gene expression in SH-SY5Y cells differentiated to dopaminergic neurons

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Summary

Introduction

Cocaine is a psychostimulant drug of abuse and its use has become a public health problem worldwide. Cocaine’s pleasurable and addictive effects are thought to be mediated mainly through dopamine (DA), which is a key neurotransmitter in reward pathways.[1] Cocaine binds the DA transporter producing an increase in DA concentration at the synapses and stimulating neurons in brain regions involved in reward and reinforcement behavior.[1,2,3]. Cocaine’s chronic and acute effects on gene expression have been studied using a broad range of animal models and experimental paradigms and procedures, including human postmortem samples.[4,5] These studies have identified gene expression changes in the brain related to diverse functional categories including synaptic communication and neuroplasticity, receptors, ion channels and transporters, cytoskeleton, extracellular matrix, oligodentrocytes and myelin, mitochondrial function, apoptosis and cell death, transcription factors and signal transduction. Two important pathways have been found affected by changes in gene expression: the mitogen-activated protein kinase (MAPK) and the synaptic long-term potentiation signal transduction pathways.[4,5]

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