Gene mutation can cause excessive alcohol drinking

UK researchers have discovered a gene that regulates alcohol consumption and, when faulty, can cause excessive drinking in mice.

The study found that normal mice drink little or no alcohol when offered a free choice between a bottle of water and a bottle of diluted alcohol.

However, mice with a mutation in the gene Gabrb1 overwhelmingly preferred drinking alcohol over water, choosing to consume almost 85 per cent of their daily fluid as drinks containing alcohol.

The research was done by a consortium of scientists from five UK universities – Imperial College London, Newcastle University, University of Sussex, UCL and University of Dundee – and the MRC Mammalian Genetics Unit at Harwell. It was funded by the Medical Research Council (MRC), Wellcome Trust and ERAB, and the findings are published in Nature Communications.

Dr Quentin Anstee, Consultant Hepatologist at Newcastle University and joint lead author, said: “It’s amazing to think that a small change in the code for just one gene can have such profound effects on complex behaviours like alcohol consumption.

“We are continuing our work to establish whether the gene has a similar influence in humans, though we know that in people, alcoholism is much more complicated as environmental factors come into play. But there is the real potential for this to guide development of better treatments for alcoholism in the future.”

Working at the MRC Mammalian Genetics Unit, a team led by Professor Howard Thomas from Imperial College London introduced subtle mutations into the genetic code at random throughout the genome and tested mice for alcohol preference.

This led the researchers to identify the gene Gabrb1, which changes alcohol preference so strongly that mice carrying either of two mutations in this gene preferred drinking a 10 per cent alcohol solution – about the strength of wine – over water.

The group showed that mice carrying this mutation were willing to work to obtain the alcoholic drink by pushing a lever and, unlike normal mice, continued to do so even over long periods. They would voluntarily consume enough alcohol in an hour to become intoxicated and have difficulty in coordinating their movements.

Gabrb1 codes for a component of the GABA_A receptor, which responds to GABA, a chemical that carries messages between brain cells.

The researchers found that the gene mutation caused the receptor to activate spontaneously, even in the absence of GABA.

These changes were particularly strong in a region of the brain that controls pleasurable emotions and reward, the nucleus accumbens.

Professor Howard Thomas, from the Department of Medicine at Imperial College London, said: “We know from previous human studies that the GABA system is involved in controlling alcohol intake. Our studies in mice show that a particular subunit of GABA_A receptor has a significant effect and, most importantly, the existence of these mice has allowed our collaborative group to investigate the mechanism involved. This is important when we come to try to modify this process first in mice and then in man.”

Professor Hugh Perry, Chair of the MRC’s Neurosciences and Mental Health Board, said: “Alcohol addiction places a huge burden on the individual, their family and wider society. There’s still a great deal we don’t understand about how and why consumption progresses into addiction, but the results of this long-running project suggest that, in some individuals, there may be a genetic component. If further research confirms that a similar mechanism is present in humans, it could help us to identify those most at risk of developing an addiction and ensure they receive the most effective treatment.”

Reference

Anstee, Q. M. et al. Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition. Nat. Commun. 4:2816 doi: 10.1038/ncomms3816 (2013).