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Gene Expression Profiling Reveals Distinct Cocaine-Responsive Genes in Human Fetal CNS Cell Types

2009; Lippincott Williams & Wilkins; Volume: 3; Issue: 4 Linguagem: Inglês

10.1097/adm.0b013e318199d863

1935-3227

Chun‐Ting Lee, Elin Lehrmann, Teruo Hayashi, Rose Amable, Shang‐Yi Tsai, Jia Chen, Joseph F. Sanchez, James Shen, Kevin G. Becker, William J. Freed,

Neurogenesis and neuroplasticity mechanisms

Objectives: Prenatal exposure to cocaine causes cytoarchitectural alterations in the developing neocortex. Previously, we reported that cocaine inhibits neural progenitor cell proliferation through oxidative endoplasmic reticulum stress and consequent down-regulation of cyclin A, whereas cyclin A expression was increased in astrocytes. In the present study, cell type-specific responses to cocaine were further explored. Methods: Gene expression profiles were examined in 5 types of cells obtained from the human fetal cerebral cortex at 20 weeks gestation. Cells were treated with 100 μM cocaine in vitro for 24 hours, followed by gene expression analysis using a human neural/stem cell/drug abuse-focused cDNA array, with verification by quantitative real-time reverse-transcriptase polymerase chain reaction. Results: Cocaine influenced transcription of distinct categories of genes in a cell type-specific manner. Cocaine down-regulated cytoskeleton-related genes including ezrin, γ2 actin, α3d tubulin, and α8 tubulin in neural and/or A2B5+ progenitor cells. In contrast, cocaine modulated immune and cell death-related genes in microglia and astrocytes. In microglia, cocaine up-regulated the immunoregulatory and proapoptotic genes interleukin-1β and BCL2-associated X protein. In astrocytes, cocaine down-regulated the immune response gene glucocorticoid receptor and up-regulated the antiapoptotic genes 14-3-3 ε and HVEM. Therefore, cell types comprising the developing neocortex show differential responses to cocaine. Conclusions: These data suggest that cocaine causes cytoskeletal abnormalities leading to disturbances in neural differentiation and migration in progenitor cells, while altering immune and apoptotic responses in glia. Understanding the mechanisms of cocaine's effects on human central nervous system cells may help in the development of therapeutic strategies to prevent or ameliorate cocaine-induced impairments in fetal brain development.