title: Nf1 regulates alcohol dependence-associated excessive drinking and gamma-aminobutyric acid release in the central amygdala in mice and is associated with alcohol dependence in humans.
abstract: BACKGROUND
  The neurofibromatosis type 1 (Nf1) gene encodes a GTPase activating protein that negatively regulates small GTPases of the Ras family.
  
  
  METHODS
  We assessed alcohol-related behaviors including alcohol sensitivity, dependent and nondependent drinking, and basal and alcohol-induced gamma-aminobutyric acid (GABA) release in the central nucleus of the amygdala (CeA) in Nf1 heterozygous null mice (Nf1(+/-)). We also investigated the associations of NF1 polymorphisms with alcohol dependence risk and severity in humans.
  
  
  RESULTS
  Nf1(+/-) mice do not differ from wild-type mice in nondependent drinking, such as 24-hour, 2-bottle choice drinking in the dark binge drinking or limited access 2-bottle choice. However, Nf1(+/-) mice failed to escalate alcohol drinking following chronic intermittent ethanol vapor exposure (CIE) to induce dependence. Alcohol acutely increases GABA release in the CeA and alcohol dependence is characterized by increased baseline GABA release in CeA. Interestingly, GABA release in Nf1(+/-) mice is greater at baseline than wild-type mice, is not elevated by induction of dependence by CIE, and failed to show alcohol-induced facilitation both before and after CIE. Additionally, we observed that multiple variants in the human NF1 gene are associated with a quantitative measure of alcohol dependence in both African Americans and European Americans.
  
  
  CONCLUSIONS
  In this translational investigation, we found that Nf1 activity regulates excessive drinking and basal and ethanol-stimulated GABA release in the mouse central amygdala. We also found that genetic variation in NF1 may confer an inherent susceptibility to the transition from nondependent to dependent drinking in humans.
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Vez
authors.initials: V
authors.lastname: Repunte-Canonigo
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Herman
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, and the VISN 4 MIRECC, Philadelphia VAMC, Philadelphia, PA 19104.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sherva
authors.affiliation: Departments of Psychiatry, Genetics, and Neurobiology, Yale University School of Medicine, VA CT Healthcare Center, West Haven, CT, and Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06516, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
authors.affiliation: Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA 02118, USA.|Departments of Neurology, Ophthalmology, Epidemiology, and Biostatistics, Boston; University Schools of Medicine and Public Health, Boston, MA 02118, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Pietro Paolo
authors.initials: PP
authors.lastname: Sanna
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage; D016514:Genes, Neurofibromatosis 1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000431:Ethanol; D005680:gamma-Aminobutyric Acid
keywords: Alcohol dependence; Amygdala; Electrophysiology; GABA; Genetic association; Presynaptic mechanisms