The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice

Abstract

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 effects of BDNF rs6265 and FGF21 rs11665896 polymorphisms on alcohol use disorder-related impulsivity in Han Chinese adults

“…Female hBDNF Val/Val mice exhibited a greater propensity toward stable ethanol self-administration than male mice of the same genotype in the operant paradigm ( 6 ). Male Met68BDNF mice exhibited a preference for alcohol over social interaction and were insensitive to the acute anxiolytic action of alcohol, which was driven by malfunction of BDNF in the ventral hippocampus of male mice ( 69 ). Therefore, further research in female patients with AUD is warranted in the future.…”

Identification of Novel BDNF-Specific Corticostriatal Circuitries

“…2009(Jeanblanc et al,. , 2013, whereas malfunctioning of BDNF/TrkB signaling in the corticostriatal regions promotes compulsive heavy use of alcohol and other alcohol-mediated behaviors (Logrip et al, 2009;Darcq et al, 2015Darcq et al, , 2016Moffat et al, 2023).…”