Ajay Mathuru What zebrafish can teach us about alcohol addiction

HEALTH AND BIOMEDICAL SCIENCES

20 Jan 2026

What Zebrafish Can Teach Us About Alcohol Addiction

An unusual animal model fills a critical gap in genetic research, paving the way for personalised medicine

Associate Professor Ajay S. Mathuru

NUS Physiology

HEALTH AND BIOMEDICAL SCIENCES

20 Jan 2026

What Zebrafish Can Teach Us About Alcohol Addiction

An unusual animal model fills a critical gap in genetic research, paving the way for personalised medicine

Associate Professor Ajay S. Mathuru

NUS Physiology

Alcohol is one of the most widely abused mind-altering substances. Beyond social and environmental influences, a person’s genetic makeup can also influence the transition from occasional after-work drink to life-threatening addiction.

Researchers have already established a link between the gene cluster chrna5-a3-b4 and substance dependence through genome-wide association studies, which scan the complete DNA sets of large human groups. However, isolating the specific contributions of individual genes within this cluster has proven challenging.

Two out of these three genes are well understood, thanks to rodent models. But the third, chrna3, has remained largely unexplored, as rodents with mutations in this gene don't survive to adulthood.

Enter an unlikely hero: zebrafish. The species lays many eggs, matures quickly and can be easily studied with light microscopy. Most importantly, zebrafish have neuro-adaptation pathways similar to the sub-cortical circuitry of humans. A new study on these small aquatic vertebrates, published in the Journal of Neuroscience, helps us to better understand how chrna3 variants may put some people at higher risk of alcohol dependence.

System translucency enabled the imaging of molecular and cellular markers in the zebrafish brain: nrp1a (green), neuroD (yellow), chrna5 (red), and nuclear DNA (violet).

"Even though they're evolutionarily distant from humans, they exhibit similar behavioural responses to alcohol, which gives us hope that this system can meaningfully inform our understanding of human disorders," said the study’s lead researcher, Associate Professor Ajay S. Mathuru from NUS Physiology.

To investigate how disruptions in the chrna3 gene affect the alcohol preferences of zebrafish, and hence humans, the researchers compared normal zebrafish with mutants that had reduced chrna3 function. In their laboratory test, both types of fish could individually choose between normal and alcohol-containing water. That’s when they discovered something surprising.

Zebrafish like alcohol too…to an extent

The normal zebrafish were attracted to alcohol at low alcohol concentrations but rapidly switched to avoiding it as concentrations increased; scientists call this a biphasic response. It is the same kind of natural response seen in mammals like humans, said Mathuru.

The mutant fish, in contrast, had an increased alcohol tolerance window. They delayed the switch from attraction to avoidance, choosing to stay in the water containing alcohol for longer periods and at higher concentrations.

Wild-type (WT) and chrna3 mutant (chrna3^C246X) fish swam in a tank with two delivery zones: stimulus (alcohol) and control (water). Entry into each zone triggered a valve to dispense the corresponding solution. Mutants spent significantly more time in the stimulus zone and self-administered larger volumes of alcohol, showing increased alcohol tolerance.

To explore why the zebrafish have this biphasic response, the researchers studied how the zebrafish move as a shoal under different alcohol concentrations. Like many species of fish, zebrafish swim in small shoals, which become tighter under stress.

How alcohol affects zebrafish

At low concentrations, the researchers observed that zebrafish swim in looser shoals. This suggests that alcohol can produce an anxiety reducing type of effect at low doses, explained Mathuru.

“If you keep adding more and more alcohol, it affects more neurons and more types of receptors,” he continued, “and at an organismal level, the sedative effects of alcohol start becoming dominant within eight or ten minutes.”

The mutants, however, were more resistant to alcohol’s behaviour-changing effects, with no behavioural change at low concentrations. The team's brain-wide analysis revealed that the mutation of chrna3, a single gene, had triggered changes across multiple neurotransmitter systems – not only in the acetylcholine pathway which chrna3 encodes, but also receptors linked to nicotine dependence and feeding behaviour.

In chrna3 mutants, an insertion causes a frameshift and premature stop in transmembrane domain 1, producing a truncated protein that lacks most transmembrane and intracellular domains and is likely damaged.

For humans, the findings suggest that the loss of chrna3 function results in heightened alcohol tolerance and a potential predisposition for multi-substance abuse and comorbid disorders.

A pathway to personalised treatment

This study has important implications for personalised medicine, an emerging field which uses an individual's genetic profile to guide treatment. A stronger understanding of the genetic underpinnings of addiction may help doctors decide which patients need more help or drug treatments, said Mathuru.

The study contributes to an emerging global effort Genetically Informed Neurobiology of Addiction (GINA) framework, by adding to its empirically tested knowledge base of genetic variants that influence addiction risk. It also proves that the zebrafish model can be a versatile and powerful tool in the evolving toolkit for neurobiological research.

References

Raine, J., Kibat, C., Banerjee, T. D., Monteiro, A., & Mathuru, A. S. (2025). chrna3 modulates alcohol response. Journal of Neuroscience, 45 (43).

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Zebrafish like alcohol too…to an extent

How alcohol affects zebrafish

A pathway to personalised treatment

References