Background The brain-derived neurotrophic factor (BDNF) Valine 66 to Methionine human polymorphism results in impaired activity-dependent BDNF release and has been linked to psychiatric disorders including depression and anxiety. We previously showed that male knock-in mice carrying the mouse Methionine homolog (Met68BDNF) exhibit excessive and compulsive alcohol drinking behaviors as compared to the wild-type Val68BDNF mice. Objective Here, we set out to determine the potential mechanism for the heightened and compulsive alcohol drinking phenotypes detected in Met68BDNF mice. Results We found that male, but not female Met68BDNF mice exhibit social anxiety-like behaviors. We further show that male Met68BDNF mice exhibit a preference for alcohol over social interaction. In contrast, alcohol place preference without an alternative social reward, is similar in male Met68BDNF and Val68BDNF mice. Since the Met68BDNF mice show social anxiety phenotypes, we tested whether alcohol reliefs anxiety similarly in Met68BDNF and Val68BDNF mice and found that male, but not female Met68BDNF mice are insensitive to the acute anxiolytic action of alcohol. Finally, we show that this acute tolerance to alcohol-dependent anxiolysis can be restored by overexpressing wild-type Val68BDNF in the ventral hippocampus (vHC) of Met68BDNF mice. Conclusions Together, our results suggest that excessive alcohol drinking in the Met68BDNF may be attributed, in part, to heighted social anxiety and a lack of alcohol-dependent anxiolysis, a phenotype that is associated with malfunction of BDNF signaling in the vHC of male Met68BDNF mice.

The brain-derived neurotrophic factor (BDNF) Valine 66 to Methionine human polymorphism results in impaired activity-dependent BDNF release and has been linked to psychiatric disorders including anxiety and alcohol dependence. We previously showed that knock-in mice carrying the mouse Methionine homolog (Met68BDNF) exhibit excessive and compulsive alcohol drinking behaviors as compared to the wild-type Val68BDNF mice. Here, we set out to determine the potential mechanism for the heightened and compulsive alcohol drinking phenotype exhibited by the Met68BDNFmice. We found that male, but not female Met68BDNF mice show social anxiety-like behaviors. We further report that male, but not female, Met68BDNF mice are resistant to the anxiolytic effects and sedative actions of alcohol as compared to Val68BDNF mice. Alcohol-dependent hypolocomotion is also reduced in Met68BDNF. In contrast, alcohol place preference is similar in Met68BDNF compared with Val68BDNF mice. Finally, we show that the anxiolytic action of alcohol is restored in Met68BDNF mice by overexpressing the wild-type Val68BDNF in the ventral hippocampus (vHC). Together, our results suggest that heighted social anxiety and a lack of alcohol-dependent anxiolysis may contribute to excessive alcohol intake by constraining normal BDNF signaling in the vHC.