Regulation of MiR-124, Let-7d, and MiR-181a in the accumbens affects the expression, extinction, and reinstatement of cocaine-induced conditioned place preference

Neuropsychopharmacology. 2011 May;36(6):1149-64. doi: 10.1038/npp.2010.250. Epub 2011 Feb 9.

Abstract

Molecular adaptations underlying drug seeking and relapse remain largely unknown. Studies highlight post-transcriptional modifications mediated by microRNAs (miRNAs) in addiction and other neurological disorders. We have previously shown that chronic cocaine suppresses miR-124 and let-7d and induces the expression of miR-181a in mesolimbic pathway. To further address the role and target gene regulation network of these miRNAs in vivo in cocaine addiction, we developed lentiviral vector (LV)-expressing miRNAs and their corresponding silencers for stable and regulatable miRNA expression. We tested in vivo miRNA gain and loss of function on cocaine-induced conditioned place preference (CPP) by localized LV-miRNA regulation in the nucleus accumbens (NAc). LV-miR-124 and let-7d expression in the NAc attenuates cocaine CPP, whereas LV-miR-181a enhances it. Silencing miRNAs by corresponding LV-miRNA silencers expressing perfect miRNA target sequences inversed this effect on cocaine CPP. Doxycycline treatment for switching off silencer expression abolished the observed behavioral changes. Behavioral changes mediated by LV-miRNA regulation resulted in dynamic alterations in transcription factors, receptors, and other effector genes involved in cocaine-induced plasticity. Our results describe a complex regulatory pathway mediated by miRNAs in cocaine-mediated neuronal adaptations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cocaine / pharmacology
  • Cocaine-Related Disorders / genetics
  • Cocaine-Related Disorders / metabolism
  • Conditioning, Psychological / drug effects*
  • Conditioning, Psychological / physiology
  • Disease Models, Animal
  • Extinction, Psychological / drug effects*
  • Extinction, Psychological / physiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Gene Regulatory Networks / drug effects
  • Gene Regulatory Networks / physiology
  • Gene Silencing / drug effects*
  • Gene Silencing / physiology*
  • HEK293 Cells
  • Humans
  • Male
  • MicroRNAs / biosynthesis*
  • MicroRNAs / metabolism*
  • MicroRNAs / physiology*
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / metabolism
  • Rats
  • Rats, Wistar

Substances

  • MIRN124 microRNA, human
  • MIRN124 microRNA, rat
  • MIRNLET7 microRNA, rat
  • MIrn181 microRNA, human
  • MicroRNAs
  • Cocaine