Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice.
BACKGROUND
Nicotine withdrawal is characterized by both affective and cognitive symptoms. Identifying genetic polymorphisms that could affect the symptoms associated with nicotine withdrawal are important in predicting withdrawal sensitivity and identifying personalized cessation therapies. In the current study we used a mouse model of a non-synonymous single nucleotide polymorphism in the translated region of the brain-derived neurotrophic factor (BDNF) gene that substitutes a valine (Val) for a methionine (Met) amino acid (Val66Met) to examine the relationship between the Val66Met single nucleotide polymorphism and nicotine dependence.


METHODS
This study measured proBDNF and the BDNF prodomain levels following nicotine and nicotine withdrawal and examined a mouse model of a common polymorphism in this protein (BDNF(Met/Met)) in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test.


RESULTS
Using the BDNF knock-in mouse containing the BDNF Val66Met polymorphism we found: (1) blunted anxiety-like behavior in BDNF(Met/Met) mice following withdrawal in three behavioral paradigms: novelty-induced hypophagia, marble burying, and the open-field test; (2) the anxiolytic effects of chronic nicotine are absent in BDNF(Met/Met) mice; and (3) an increase in BDNF prodomain in BDNF(Met/Met) mice following nicotine withdrawal.


CONCLUSIONS
Our study is the first to examine the effect of the BDNF Val66Met polymorphism on the affective symptoms of withdrawal from nicotine in mice. In these mice, a single-nucleotide polymorphism in the translated region of the BDNF gene can result in a blunted withdrawal, as measured by decreased anxiety-like behavior. The significant increase in the BDNF prodomain in BDNF(Met/Met) mice following nicotine cessation suggests a possible role of this ligand in the circuitry remodeling after withdrawal.
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
Bridgin G
BG
Lee
Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY;
Agustin
A
Anastasia
Department of Medicine, Weill Cornell Medical College of Cornell University, New York, NY;
Barbara L
BL
Hempstead
Department of Psychiatry, Weill Cornell Medical College of Cornell University, New York, NY.
Francis S
FS
Lee
Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; blendy@mail.med.upenn.edu.
Julie A
JA
Blendy
D000818:Animals; D001007:Anxiety / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D005260:Female; D055879:Gene Knock-In Techniques; D008297:Male; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009538:Nicotine / Q000008:administration & dosage*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000523:psychology; D014029:Tobacco Use Disorder / Q000235:genetics / Q000523:psychology; D014633:Valine / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; D009538:Nicotine; D008715:Methionine; D014633:Valine