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NIH Study Identifies Gene Variant Linked to Compulsive Drinking


Alcohol use disorder affects about 16.6 million adults in the United States.


Brain-derived neurotrophic (BDNF) plays a role in the survival of existing neurons and the growth of new neurons and synapses, the junctures through which cell-to-cell communication occurs. The human form of this gene variant, Met66BDNF, leads to a reduction in the normal function of BDNF in the brain and is associated with several psychiatric disorders, including schizophrenia and depression.  According to results of a recent study in the mouse, and  published online in Biological Psychiatry (11 June 2015), carrying a gene variant that affects the release of a specific brain protein may put one at greater risk of developing an alcohol use disorder. The study found that mice carrying the Met68BDNF gene variant, which reduces the release of BDNF, would consume excessive amounts of alcohol, despite negative consequences.


In a study reported earlier this year, NIH-supported scientists found that adolescent binge drinking was linked to lower levels of brain-derived neurotrophic factor, and these changes persisted into adulthood.


For the study, the authors tested the role of BDNF in alcohol addiction by creating a “knock-in“ mouse carrying Met68BDNF. In this variant, the amino acid valine (Val) is replaced by methionine (Met) in a specific position within the protein sequence of BDNF, resulting in reduced activity-dependent BDNF release. Results showed that these “knock-in“ mice drank more alcohol, even when the alcohol was treated with bitter-tasting quinine. This suggests Met68BDNF carriers compulsively drink alcohol despite aversive consequences. According to the authors, the effect of the genetic mutation seemed to be specific to alcohol consumption since the mice did not differ in their consumption of other fluids, or exhibit differences in levels of anxiety or compulsive behaviors. Significantly, the authors were able to reverse compulsive alcohol drinking in the mice using gene delivery and pharmacology. Increasing levels of BDNF in the ventromedial portion of the prefrontal cortex, a brain region involved in compulsive drug and alcohol seeking, returned the mice to moderate levels of alcohol intake. In addition, by administering a pharmaceutical compound developed to mimic the action of BDNF, it was possible to put a stop to compulsive drinking behaviors. This compound (LM22A-4) may have potential as a therapeutic for humans as it appears to reduce compulsive alcohol drinking without a generalized effect on motivation. According to the authors, knowing whether patients carry a gene that results in decreased BDNF function could help in tailoring alcohol prevention and treatment strategies in the future.



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