Downregulation of mu opioid receptor by RNA interference in the ventral tegmental area reduces ethanol consumption in mice

A. W. Lasek, P. H. Janak, L. He, Jennifer Whistler, U. Heberlein

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Pharmacological and genetic studies have implicated the mu opioid receptor (MOR) in the regulation of ethanol intake in animal models and humans. Non-specific antagonists of opioid receptors have been shown to affect ethanol consumption when infused directly into the ventral tegmental area (VTA) of rats. However, administration of MOR-selective antagonists into the VTA has yielded mixed results. We used RNA interference (RNAi) to specifically decrease levels of MOR messenger RNA in the VTA of mice and examined the effect on ethanol consumption in a two-bottle choice paradigm. Mice were injected in the VTA with lentivirus expressing either a small hairpin RNA (shRNA) targeting MOR or a control shRNA. One week after virus injection, mice were examined for ethanol consumption in a two-bottle choice experiment with increasing concentrations of ethanol over the course of 1 month. Expression of an shRNA targeting MOR in the VTA led to a significant reduction in ethanol consumption. These results strengthen the hypothesis that MOR in the VTA is one of the key brain substrates mediating alcohol consumption. The RNAi combined with lentiviral delivery can be used successfully in brain to effect a sustained reduction in expression of specific genes for behavioral analysis.

Original languageEnglish (US)
Pages (from-to)728-735
Number of pages8
JournalGenes, Brain and Behavior
Volume6
Issue number8
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Keywords

  • Ethanol consumption
  • Lentivirus
  • Opioid receptor
  • RNA interference
  • Ventral tegmental area

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

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