The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation

Vincent Warnault; Emmanuel Darcq; Nadege Morisot; Khanhky Phamluong; Linda Wilbrecht; Stephen M Massa; Frank M Longo; Dorit Ron

doi:10.1016/j.biopsych.2015.06.007

The BDNF Valine 68 to Methionine Polymorphism Increases Compulsive Alcohol Drinking in Mice That Is Reversed by Tropomyosin Receptor Kinase B Activation

Biol Psychiatry. 2016 Mar 15;79(6):463-73. doi: 10.1016/j.biopsych.2015.06.007. Epub 2015 Jun 12.

Authors

Vincent Warnault¹, Emmanuel Darcq¹, Nadege Morisot¹, Khanhky Phamluong¹, Linda Wilbrecht², Stephen M Massa³, Frank M Longo⁴, Dorit Ron⁵

Affiliations

¹ Department of Neurology, University of California, San Francisco, San Francisco.
² Department of Psychology, University of California, Berkeley, Berkeley.
³ 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.
⁴ Department of Neurology and Neurological Sciences (FML), Stanford University School of Medicine, Stanford, California.
⁵ Department of Neurology, University of California, San Francisco, San Francisco. Electronic address: dorit.ron@ucsf.edu.

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.

Keywords: Addiction; Alcohol; BDNF; Ethanol; Growth factor; Polymorphism.

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*
Alcoholism / genetics
Alleles
Animals
Benzamides / pharmacology
Brain-Derived Neurotrophic Factor / genetics*
Compulsive Behavior*
Disease Models, Animal
Methionine / genetics
Mice
Mice, Transgenic
Polymorphism, Single Nucleotide
Protein-Tyrosine Kinases / metabolism*
Receptor, trkB / genetics*
Valine / genetics

Substances

Benzamides
Brain-Derived Neurotrophic Factor
N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide
Methionine
Protein-Tyrosine Kinases
Receptor, trkB
Valine

Abstract

Publication types

MeSH terms

Substances

Grants and funding