1 May 2009

Adam Fletcher By

Appeared in BioNews 510

Neuroscientists at the University of California, San Francisco, and the Ernest Gallo Research Center, Emeryville, US, have published a study in the journal Cell describing a new gene that influences ethanol sensitivity in the fruit fly Drosophila melanogaster. The work offers tantalising hope that the same regulatory mechanisms might apply to humans too. Alcohol abuse disorders (AUDs) are crippling for individuals affected and society at large. Currently, few medical treatments exist that specifically target addiction, and the biology of the disease is unclear.

The scientists began their work with a test devised to measure 'drunkenness' in Drosophila. Flies respond to alcohol in a similar manner to mammals; low doses of the drug result in hyperactivity, whilst higher doses cause decreased activity and eventual loss of postural control and sedation. The researchers first introduced random mutations throughout the genome of hundreds of flies, and then measured the ability of alcohol to induce drowsiness in the insects.

One strain of fly in the experiment was shown to be hyper-resistant to sedation. The scientists pinpointed the defect in these flies as being within a gene they dubbed 'happyhour', so named because its mutation resulted in flies 'able to imbibe significantly more alcohol than wild-type controls before succumbing to sedative effects'. The researchers discovered that the happyhour gene affects the 'EGF' (Epidermal Growth Factor) pathway, already known to be involved in cell proliferation and cancer.

Further experiments showed that the flies' resistance to sedation was because the happyhour protein was not being sufficiently manufactured. Tellingly, replacing the protein in affected flies could reverse the phenomenon. The human equivalent of the happyhour protein might also be scarce in alcoholics.

'People who are very sensitive to alcohol tend to drink less - that's the person who gets drunk on one glass of wine', says Professor Robert Swift, psychiatrist at Brown University, Rhode Island, Providence, US. 'The person who can drink everybody under the table - that's that person who is more likely to become an alcoholic', he said.

Administration of two EGF inhibitors, erlotinib (brand name Tarceva) and gefitinib (Iressa) to alcoholic flies restored their sensitivity to ethanol to that of their normal cousins. Furthermore, feeding erlotinib to rats decreased their preference for ethanol even when made freely available. The two drugs are FDA-approved chemotherapy agents, used in the treatment of lung cancers. Able to cross the blood-brain barrier, and being well tolerated, they highlight a potential therapeutic avenue for the treatment of AUDs in humans.

Since 1998, principal investigator Professor Ulrike Heberlein's lab has identified two other genes - 'cheapdate' and 'hangover' - that also influence sensitivity to alcohol in fruitflies.