title: AKT signaling pathway in the nucleus accumbens mediates excessive alcohol drinking behaviors.
abstract: BACKGROUND
  Neuroadaptations within the nucleus accumbens (NAc) have been implicated in molecular mechanisms underlying the development and/or maintenance of alcohol abuse disorders. We recently reported that the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in the NAc of rodents, after exposure to alcohol, contributes to alcohol drinking behaviors. The kinase AKT is a main upstream activator of the mTORC1 pathway. We therefore hypothesized that the activation of AKT in the NAc in response to alcohol exposure plays an important role in mechanisms that underlie excessive alcohol consumption.
  
  
  METHODS
  Western blot analysis was used to assess the phosphorylation levels of enzymes. Acute exposure of mice to alcohol was achieved by the administration of 2 g/kg alcohol intraperitoneally (i.p.). Two-bottle choice and operant self-administration procedures were used to assess drinking behaviors in rats.
  
  
  RESULTS
  We found that acute systemic administration of alcohol and recurring cycles of excessive voluntary consumption of alcohol and withdrawal result in the activation of AKT signaling in the NAc of rodents. We show that inhibition of AKT or its upstream activator, phosphatidylinositol-3-kinase (PI3K), within the NAc of rats attenuates binge drinking as well as alcohol but not sucrose operant self-administration.
  
  
  CONCLUSIONS
  Our results suggest that the activation of the AKT pathway in the NAc in response to alcohol exposure is an important contributor to the molecular mechanisms underlying alcohol-drinking behaviors. AKT signaling pathway inhibitors are therefore potential candidates for drug development for the treatment of alcohol use and abuse disorders.
authors.affiliation: Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, California, USA.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Neasta
authors.forename: Sami
authors.initials: S
authors.lastname: Ben Hamida
authors.forename: Quinn V
authors.initials: QV
authors.lastname: Yowell
authors.forename: Sebastien
authors.initials: S
authors.lastname: Carnicella
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism* / Q000503:physiopathology; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism* / Q000503:physiopathology*; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000506:poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009714:Nucleus Accumbens / Q000378:metabolism / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D012263:Ribonucleosides / Q000008:administration & dosage / Q000494:pharmacology; D012646:Self Administration / Q000379:methods / Q000523:psychology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013395:Sucrose / Q000008:administration & dosage; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D047428:Protein Kinase Inhibitors; D012263:Ribonucleosides; C023764:triciribine; D000431:Ethanol; D013395:Sucrose; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin