title: The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation.
abstract: BACKGROUND
  The valine 66 to methionine (Met) polymorphism within the brain-derived neurotrophic factor (BDNF) sequence reduces activity-dependent BDNF release and is associated with psychiatric disorders in humans. Alcoholism is one of the most prevalent psychiatric diseases. Here, we tested the hypothesis that this polymorphism increases the severity of alcohol abuse disorders.
  
  
  METHODS
  We generated transgenic mice carrying the mouse homolog of the human Met66BDNF allele (Met68BDNF) and used alcohol-drinking paradigms in combination with viral-mediated gene delivery and pharmacology.
  
  
  RESULTS
  We found that Met68BDNF mice consumed excessive amounts of alcohol and continued to drink despite negative consequences, a hallmark of addiction. Importantly, compulsive alcohol intake was reversed by overexpression of the wild-type valine68BDNF allele in the ventromedial prefrontal cortex of the Met68BDNF mice or by systemic administration of the tropomyosin receptor kinase B agonist, LM22A-4.
  
  
  CONCLUSIONS
  Our findings suggest that carrying this BDNF allele increases the risk of developing uncontrolled and excessive alcohol drinking that can be reversed by directly activating the BDNF receptor, tropomyosin receptor kinase B. Importantly, this work identifies a potential therapeutic strategy for the treatment of compulsive alcohol drinking in humans carrying the Met66BDNF allele.
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco.
authors.forename: Vincent
authors.initials: V
authors.lastname: Warnault
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Darcq
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco.
authors.forename: Nadege
authors.initials: N
authors.lastname: Morisot
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco.
authors.forename: Khanhky
authors.initials: K
authors.lastname: Phamluong
authors.affiliation: Department of Psychology, University of California, Berkeley, Berkeley.
authors.forename: Linda
authors.initials: L
authors.lastname: Wilbrecht
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco; Laboratory for Computational Neurochemistry and Drug Discovery and Department of Veterans Affairs Medical Center, University of California, San Francisco, San Francisco.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.affiliation: Department of Neurology and Neurological Sciences (FML), Stanford University School of Medicine, Stanford, California.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco. Electronic address: dorit.ron@ucsf.edu.
authors.forename: Dorit
authors.initials: D
authors.lastname: Ron
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics; D000483:Alleles; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003192:Compulsive Behavior; D004195:Disease Models, Animal; D008715:Methionine / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics*; D014633:Valine / Q000235:genetics
chemical_list: D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; C585903:N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide; D008715:Methionine; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; D014633:Valine
keywords: Addiction; Alcohol; BDNF; Ethanol; Growth factor; Polymorphism