microRNAs miR-124, let-7d and miR-181a regulate cocaine-induced plasticity

Mol Cell Neurosci. 2009 Dec;42(4):350-62. doi: 10.1016/j.mcn.2009.08.009. Epub 2009 Aug 22.


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.

MeSH terms

  • Animals
  • Base Sequence
  • Brain / anatomy & histology
  • Brain / physiology
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cocaine / pharmacology*
  • Dopamine Uptake Inhibitors / pharmacology*
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics*
  • Neuronal Plasticity / physiology
  • Oligonucleotide Array Sequence Analysis
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Dopamine D3 / genetics
  • Receptors, Dopamine D3 / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Reproducibility of Results
  • Substance-Related Disorders / physiopathology


  • Brain-Derived Neurotrophic Factor
  • Dopamine Uptake Inhibitors
  • MIRN124 microRNA, rat
  • MIRNLET7 microRNA, rat
  • MicroRNAs
  • RE1-silencing transcription factor
  • RNA Precursors
  • Receptors, Dopamine D3
  • Repressor Proteins
  • Cocaine