Although the effects of alcohol have been enjoyed around the world for thousands of years, addiction can lead to significant social and medical problems. Alcohol affects a number of different biochemical pathways and a better understanding of the factors that contribute to alcohol abuse and addiction could lead to improved treatments. Since a lower initial response to the effects of alcohol has been found to correlate with increased risk of future alcoholism, identification of the genes and pathways involved in the acute response might throw light on the genetic factors contributing to addiction. The fruit fly, Drosophila melanogaster, reacts in much the same way as mammals to acute ethanol exposure and a team led by Ulrike Heberlein at the University of California is using the fly to explore the links between genetic make-up and response to alcohol. Their latest find is that flies with a mutant version of a gene that they have designated ‘happyhour’ are less sensitive to the sedative effects of alcohol than flies with a normal copy of the gene. Further studies showed that the epidermal growth factor (EGF)-signalling pathway regulates ethanol sensitivity in Drosophila and that the happyhour protein inhibits this pathway.
The EGF receptor (EGFR) is overexpressed in certain types of carcinoma and drugs that inhibit the EGFR tyrosine kinase such as erlotinib (Tarceva™) and gefitinib (Iressa™) have been successfully developed for the treatment of cancer. The team were able to show that treatment with erlotinib increased acute alcohol sensitivity in both fruit flies and mice and, importantly, also reduced alcohol consumption in a rat model of alcoholism. Although it is not yet clear exactly how alcohol exerts its influence on the EGF pathway or how these changes lead to changes in behaviour after alcohol consumption, the authors suggest that inhibition of the pathway could provide a potential treatment for alcohol addiction. Both erlotinib and gefitinib are well-tolerated and are known to cross the blood-brain barrier. The study is published in the journal Cell.