Increased risk of developing alcohol addiction linked to gene mutation

Researchers from the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) report that the gene, CHRNA3, acts as a key regulator of alcohol sensitivity. Published in the Journal of Neuroscience, the study provides long-sought experimental evidence to back up human genetic studies, linking CHRNA3 function changes to measurable differences in innate alcohol sensitivity.
The study was led by Associate Professor Ajay S. Mathuru from the Department of Physiology at NUS Medicine with first author, Dr. Joshua Raine, Research Fellow, and Dr. Caroline Kibat, Senior Research Fellow, from the same department. The team found that mutations in the gene chrna3, a nicotinic acetylcholine receptor gene expressed in the nervous system, are associated with lowered sensitivity to alcohol in a preclinical laboratory model.
To determine if genetic factors can contribute to developing alcohol use disorders, the researchers utilised a two-choice assay where it is possible to self-administer alcohol voluntarily. They quantified avoidance versus attraction behaviour and analysed brain gene expression for key neurotransmitter receptors.
In normal conditions, brief attraction to alcohol followed by rapid avoidance as the dose rises, was observed. In contrast, preclinical laboratory models with mutations in chrna3 delay this switch to avoidance, self-administering alcohol for much longer and tolerating higher concentrations.
The mutation was associated with altered brain expression of glutamatergic and GABAergic receptor genes, which regulate excitatory and inhibitory signalling respectively, and reduced alcohol’s typical effects on behaviour by weakening the calming effect at low doses. These findings indicate that normal chrna3 function helped control alcohol exposure and may underlie individual differences in alcohol sensitivity.
By linking the chrna3 gene to measurable behavioural and brain changes, this study strengthens the biological understanding of addiction risk and offers insights into genetic predisposition to alcohol dependence.
“Our study provides direct experimental evidence that chrna3 regulates alcohol sensitivity,” said Assoc Prof Mathuru. “Variants altering this gene’s function may increase the risk of developing alcohol use disorders in humans, a possibility that needs further investigation. Finding such risk factors can help develop more effective prevention and treatment strategies.” Assoc Prof Mathuru is a Joint Principal Investigator at Institute of Molecular and Cell Biology, A*STAR. He holds appointments with N.1 Institute for Health at NUS, the Institute of Digital Medicine (WisDM), and the Healthy Longevity Translational Research Programme at NUS Medicine. Collaborators of the study include Professor Antónia Monteiro and Dr Tirtha Das Banerjee from the Department of Biological Sciences at NUS.
The refined self-administration assay used in this study provides a cost-effective technique with faster turn-around times to uncover how specific genes modulate addiction-associated behaviours. It can complement other approaches to improve efficiency and guide future targeted therapies.
Building on this work, the team aims to analyse CHRNA3 variants in humans for similar alcohol sensitivity. They have extended their research to map reward and avoidance circuits and to dissect interactions using single and combined mutations in CHRNA5-CHRNA3-CHRNB4 gene cluster linked to substance addiction. The team’s future work aims to uncover mechanistic links across neurotransmitter systems altered in these mutants, assess impacts on other behaviours, and examine relevance to co-occurring human conditions - informing personalised preventive strategies for individuals with such genetic predispositions

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