A gene mutation for excessive alcohol drinking found
Sussex researchers are among a team of UK scientists who have discovered a gene that regulates alcohol consumption and, when faulty, can cause excessive drinking. They have also identified the mechanism underlying this phenomenon.
The study showed that normal mice show no interest in alcohol and 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 genetic mutation to the gene Gabrb1 overwhelmingly preferred drinking alcohol over water, choosing to consume almost 85% of their daily fluid as drinks containing alcohol.
The consortium of researchers from five UK universities – Imperial College London, Newcastle University, University of Sussex, University College London and University of Dundee – and the MRC Mammalian Genetics Unit (MGU) at Harwell, funded by the Medical Research Council (MRC), Wellcome Trust and ERAB, publish their findings today (26 November) in Nature Communications.
University of Sussex psychologist Professor Dai Stephens, who leads the Medical Research Council Addiction cross-university team working on how chemical receptors in the brain influence drug abuse, said: “Why some people abuse alcohol while others are readily able to control their drinking is still something of a mystery for science.
“This research shows that really subtle changes that can arise quite spontaneously in a gene can have catastrophic effects on normal biological function, and precipitate excessive drinking.”
Dr Quentin Anstee, Consultant Hepatologist at Newcastle University, joint lead author said: “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 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 Gabrb, which changes alcohol preference so strongly that mice carrying either of two single base-pair point mutations in this gene preferred drinking alcohol (10% ethanol v/v - about the strength of wine), over water.
The group showed that mice carrying this mutation were willing to work to obtain the alcohol-containing drink by pushing a lever and, unlike normal mice, continued to do so even over long periods. They would voluntarily consume sufficient alcohol in an hour to become intoxicated and even have difficulty in coordinating their movements.
The cause of the excessive drinking was tracked down to a single point mutation in the Gabrb1 gene that encodes for a particular subtype (beta 1) of receptor that responds to the brain’s most important inhibitory chemical, GABA, which regulates brain activity.
The researchers found that the mutation caused the receptor to activate spontaneously even when the usual GABA trigger was not present.
These changes were particularly strong in the region of the brain that controls pleasurable emotions and reward, the nucleus accumbens. Dr Anstee explained: “As the electrical signal from these receptors increases, so does the desire to drink to such an extent that mice will actually work to get the alcohol, for much longer than we would have expected.”
Professor Stephens said: "Perhaps the mice drink so much because they are attempting to activate their reward systems, which are chronically under-performing as a result of the mutation.
“While it is unlikely that the identical genetic fault is a major cause of human alcohol abuse, this research indicates that when certain GABA-A receptors become leaky, the ability to know when to stop drinking seems impaired. Unfortunately, no drugs are available at present that could reduce the leakiness of the particular receptors involved, without dangerous side effects from interfering with other related receptors. That might be an obvious target for future work.”
Notes for editors
- 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).
- The MRC, Economic and Social Research Council and Alcohol Research UK currently have a highlight notice calling for research linking harms caused by alcohol to drinking behaviours.
- The MRC Centenary Timeline
- University of Sussex Press Office Jacqui Bealing and Maggie Clune, email: firstname.lastname@example.org, Tel: 01273 678888