Nucleus accumbens AGS3 expression drives ethanol seeking through G betagamma

Proc Natl Acad Sci U S A. 2008 Aug 26;105(34):12533-8. doi: 10.1073/pnas.0706999105. Epub 2008 Aug 21.


Approximately 90% of alcoholics relapse within 4 years, in part because of an enhanced motivation to seek alcohol (EtOH). A novel G protein modulator (Gpsm1/AGS3) was up-regulated in the rat nucleus accumbens core (NAcore) but not in other limbic nuclei during abstinence from operant EtOH self-administration. Furthermore, NAcore AGS3 knockdown reduced EtOH seeking to pre-abstinence levels in a novel rat model of compulsive, human EtOH seeking. AGS3 can both inhibit G protein G i alpha-mediated signaling and stimulate G betagamma-mediated signaling. Accordingly, sequestration of G betagamma, but not G i alpha knockdown, significantly reduced EtOH seeking to pre-abstinence levels. Thus, AGS3 and G betagamma are hypothesized to gate the uncontrolled motivation to seek EtOH during abstinence. AGS3 up-regulation during abstinence may be a key determinant of the transition from social consumption to compulsion-like seeking during relapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alcohol Drinking / genetics*
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology*
  • Ethanol
  • GTP-Binding Protein Regulators / genetics
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein beta Subunits / metabolism*
  • GTP-Binding Protein gamma Subunits / metabolism*
  • Male
  • Nucleus Accumbens / chemistry
  • Nucleus Accumbens / metabolism*
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Up-Regulation


  • Carrier Proteins
  • GTP-Binding Protein Regulators
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Gpsm1 protein, rat
  • Ethanol
  • GTP-Binding Protein alpha Subunits, Gi-Go