Image: Wikipedia - André Karwath In fact not just one, but a whole bunch of them! Whilst not immediately obvious, researchers at North Carolina State and Boston universities have found them pretty useful in the study of alcohol tolerance. Recognising the difficulties of genome-wide association studies (GWAS) in humans, the team used Drosphila as a model to investigate the genetic networks underlying responses to ethanol. By comparing changes in gene expression to differences in phenotypic response, a number of genes were identified that correlated with variation in susceptibility, as well as induction of tolerance, to alcohol.
Importantly, many of the genes identified have human orthologues, enabling focused analysis of their roles in human responses to alcohol. Indeed, the team found that polymorphisms in one of these, malic enzyme-1, correlated with alcohol consumption in humans.
The study, published in the October print edition of the journal Genetics, paves the way to greater insight into the genetic factors that may predispose individuals to alcoholism. It may also reveal mechanisms for the negative side-effects of alcohol such as ‘fatty liver’, a precursor to cirrhosis.
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.
At this time of year many smokers will be trying to quit, and a recent study suggests that some will find it harder than others. Most smokers believe that smoking improves concentration and, undoubtedly, withdrawal symptoms cause feelings of irritability and agitation that make concentration difficult. When nicotine levels fall, smokers experience withdrawal symptoms which can only be alleviated by another cigarette. Scientists at the Abramson Cancer Center and Department of Psychiatry in the University of Pennsylvania School of Medicine had previously shown that smokers with a polymorphism in the catechol-O-methyltransferase (COMT) gene that results in a methionine to valine substitution suffer more from concentration problems associated with nicotine withdrawal. COMT is one of a number of enzymes that degrade catecholamines such as dopamine, and individuals with the valine COMT variant degrade dopamine at a faster rate than those with the methionine variant. The group has now used functional magnetic resonance imaging to examine brain function in smokers both during periods of abstinence and normal smoking. During the brain scans, the subjects were asked to hold in their minds a series of complex geometrical figures. The results showed that smokers with the valine variant suffered greater deficits in working memory and brain function when they had refrained from smoking for 14 or more hours, and this group also reported more severe withdrawal symptoms. The findings are published in the journal Molecular Psychiatry.
Smokers with the valine COMT variant are less responsive to existing therapies for smoking cessation and the study suggests that this group could be helped to quit by COMT inhibitors.
Cigarette smoking is recognised to be a major risk factor for disease, but once started, the habit is hard to quit. Nicotine is mainly responsible for dependence on tobacco and, historically, nicotine addiction has been one of the hardest to break. Now scientists at Scripps Florida have found that blocking the orexin A receptor in animal models abolishes the stimulatory effects of nicotine on brain reward circuitries and significantly reduces the desire for nicotine. In the study, the selective orexin A receptor antagonist, SB-334867, was found to decrease nicotine self-administration in rats and also reduced motivation to seek and obtain the drug.
If Orexin A is also involved in sustaining nicotine addiction in human smokers, blocking the orexin A receptor could be a potential target for developing new smoking cessation treatments. The Scripps group are hoping to discover new orexin A antagonists that would help smokers quit the habit. The study was published in the Nov 24 online Early Edition of the Proceedings of the National Academy of Sciences.
The orexin A receptor appears to be widely involved in regulating motivated behaviour and other studies have shown that SB-334867 also reduces alcohol-seeking behaviour in rats.