microRNAs miR-124, let-7d and miR-181a regulate cocaine-induced plasticity.
MicroRNAs play key regulatory roles in cellular processes including neurogenesis, synapse development and plasticity in the brain. Psychostimulants induce strong neuroadaptive changes through a surfeit of gene regulatory mechanisms leading to addiction. MicroRNA profiling for identifying miRNAs regulating cocaine-induced, plasticity-related genes revealed significant regulation of a set of miRNAs upon cocaine administration, especially let-7d, miR-181a and the brain-specific miR-124. These miRNAs target many genes involved in cocaine addiction. Precursor and mature miRNA quantification by qRT-PCR showed that miR-124 and let-7d are significantly downregulated, whereas miR-181a is induced in the mesolimbic dopaminergic system under chronic cocaine administration. Results were confirmed by in situ hybridization, Northern blots, FISH analysis and RNase protection assay. Using lentiviral-mediated miRNA expression, we show a significant downregulation of BDNF and D3R both at mRNA and protein levels by miR-124 and let-7d, respectively. Our data suggest that miR-124, let-7d and miR-181a may be involved in a complex feedback loop with cocaine-responsive plasticity genes, highlighting the possibility that some miRNAs are key regulators of the reward circuit and may be implicated in addiction.
Chandrasekar
Vijay
V
Division of Biochemistry, Department of Medicine, University of Fribourg, Rue du Musée 5, Chemin du Musée 5, CH-1700 Fribourg, Switzerland.
Dreyer
Jean-Luc
JL
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D019966:Substance-Related Disorders / Q000503:physiopathology; D000099229:RE1-Silencing Transcription Factor
D019208:Brain-Derived Neurotrophic Factor; D003042:Cocaine; D018765:Dopamine Uptake Inhibitors; D035683:MicroRNAs; D012322:RNA Precursors; D050637:Receptors, Dopamine D3; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C548144:MIRN124 microRNA, rat; C548145:MIRNLET7 microRNA, rat