title: Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks.
abstract: BACKGROUND
  A systems biology approach based on the assembly and interrogation of gene regulatory networks, or interactomes, was used to study neuroadaptation processes associated with the transition to alcohol dependence at the molecular level.
  
  
  RESULTS
  Using a rat model of dependent and non-dependent alcohol self-administration, we reverse engineered a global transcriptional regulatory network during protracted abstinence, a period when relapse rates are highest. We then interrogated the network to identify master regulator genes that mechanistically regulate brain region-specific signatures associated with dependent and non-dependent alcohol self-administration. Among these, the gene coding for the glucocorticoid receptor was independently identified as a master regulator in multiple brain regions, including the medial prefrontal cortex, nucleus accumbens, central nucleus of the amygdala, and ventral tegmental area, consistent with the view that brain reward and stress systems are dysregulated during protracted abstinence. Administration of the glucocorticoid antagonist mifepristone in either the nucleus accumbens or ventral tegmental area selectively decreased dependent, excessive, alcohol self-administration in rats but had no effect on non-dependent, moderate, alcohol self-administration.
  
  
  CONCLUSIONS
  Our study suggests that assembly and analysis of regulatory networks is an effective strategy for the identification of key regulators of long-term neuroplastic changes within specific brain regions that play a functional role in alcohol dependence. More specifically, our results support a key role for regulatory networks downstream of the glucocorticoid receptor in excessive alcohol drinking during protracted alcohol abstinence.
authors.affiliation: Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA. Canonigo@scripps.edu.
authors.forename: Vez
authors.initials: V
authors.lastname: Repunte-Canonigo
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY, 10027, USA. wks2105@columbia.edu.|Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. wks2105@columbia.edu.
authors.forename: William
authors.initials: W
authors.lastname: Shin
authors.affiliation: Committee for the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA. leandro@scripps.edu.|Current affiliation: Intramural Research Program, NIDA-NIH, Baltimore, MD, 21224, USA. leandro@scripps.edu.
authors.forename: Leandro F
authors.initials: LF
authors.lastname: Vendruscolo
authors.affiliation: Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. celine.lefebvre@igr.fr.|Current affiliation: Inserm Unit U981, Gustave Roussy Institute, Villejuif, France. celine.lefebvre@igr.fr.
authors.forename: Celine
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA. lenav@scripps.edu.
authors.forename: Lena
authors.initials: L
authors.lastname: van der Stap
authors.affiliation: Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA. Tomoya@scripps.edu.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Committee for the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA. schlos@scripps.edu.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Schlosburg
authors.affiliation: Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. malvarez@c2b2.columbia.edu.
authors.forename: Mariano
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Committee for the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA. george.koob@nih.gov.|Current affiliation: National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, 20852, USA. george.koob@nih.gov.
authors.forename: George F
authors.initials: GF
authors.lastname: Koob
authors.affiliation: Department of Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.|Department of Biomedical Informatics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.|Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.|Department of Biochemistry and Molecular Biophysics, Hammer Health Sciences Center, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.|Cancer Regulatory Network Program, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA. califano@c2b2.columbia.edu.|The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. califano@c2b2.columbia.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Molecular and Integrative Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA. psanna@scripps.edu.
authors.forename: Pietro Paolo
authors.initials: PP
authors.lastname: Sanna
mesh_terms: D000437:Alcoholism / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage; D053263:Gene Regulatory Networks; D005809:Genes, Regulator; D006727:Hormone Antagonists / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics; D012646:Self Administration
chemical_list: D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D000431:Ethanol