Overexpression of miR-9 in the Nucleus Accumbens Increases Oxycodone Self-Administration

Int J Neuropsychopharmacol. 2019 Jun 3;22(6):383-393. doi: 10.1093/ijnp/pyz015.

Abstract

Background: There is an urgent need to identify factors that increase vulnerability to opioid addiction to help stem the opioid epidemic and develop more efficient pharmacotherapeutics. MicroRNAs are small non-coding RNAs that regulate gene expression at a posttranscriptional level and have been implicated in chronic drug-taking in humans and in rodent models. Recent evidence has shown that chronic opioid treatment regulates the microRNA miR-9. The present study was designed to test the hypothesis that miR-9 in the nucleus accumbens potentiates oxycodone addictive-like behavior.

Methods: We utilized adeno-associated virus (AAV) to overexpress miR-9 in the nucleus accumbens of male rats and tested the effects on intravenous self-administration of the highly abused prescription opioid, oxycodone, in 1-hour short-access followed by 6-h long-access sessions, the latter of which leads to escalation of drug intake. In separate rats, we assessed the effects of nucleus accumbens miR-9 overexpression on mRNA targets including RE1-silencing transcription factor (REST) and dopamine D2 receptor (DRD2), which have been shown to be regulated by drugs of abuse.

Results: Overexpression of miR-9 in the nucleus accumbens significantly increased oxycodone self-administration compared with rats expressing a control, scrambled microRNA. Analysis of the pattern of oxycodone intake revealed that miR-9 overexpression increased "burst" episodes of intake and decreased the inter-infusion interval. Furthermore, miR-9 overexpression decreased the expression of REST and increased DRD2 in the nucleus accumbens at time points that coincided with behavioral effects.

Conclusions: These results suggest that nucleus accumbens miR-9 regulates oxycodone addictive-like behavior as well as the expression of genes that are involved in drug addiction.

Keywords: DRD2; REST; addiction; microRNA; opioids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Addictive / chemically induced
  • Behavior, Addictive / physiopathology*
  • Dependovirus / genetics
  • Genetic Vectors / administration & dosage
  • Male
  • MicroRNAs / biosynthesis*
  • MicroRNAs / physiology*
  • Microinjections
  • Nucleus Accumbens / metabolism*
  • Oxycodone / pharmacology*
  • Rats
  • Receptors, Dopamine D2 / biosynthesis
  • Repressor Proteins / biosynthesis
  • Self Administration

Substances

  • DRD2 protein, rat
  • MIRN9 microRNA, rat
  • MicroRNAs
  • RE1-silencing transcription factor
  • Receptors, Dopamine D2
  • Repressor Proteins
  • Oxycodone