Studies of the global gene expression changes in alcoholic human brain and blood

Alcohol is known as a drug subject to addiction. Long-term excessive drinking may cause alcohol tolerance, dependence, and craving. Neuroadaptations underlying these effects are likely due to changes at the gene expression level in the brain. Previous gene expression studies in the post-mortem human brain of alcoholics demonstrated that several gene families were altered by alcohol abuse (Lewohl et al. 2000; Mayfield et al. 2002). However, it is not clear how individual variability contributes to the observed changes. In addition, most changes in alcoholic human brain were relatively small. It is not clear if patterns of gene expression have sufficient power to discriminate control from alcoholic individuals. Around 10~15% of alcohol abusers develop liver cirrhosis. It is still unknown how concomitant liver cirrhosis may alter gene expression level in alcoholic human brain on a global scale. In the present study, microarray analysis was first performed on both frontal and motor cortex. A clustering analysis of cases suggested that patterns of gene expression changes in the frontal cortex were more consistent than these in motor cortex. Therefore the subsequent studies were focused on the frontal cortex. The sample size was increased to 14 uncomplicated alcoholics and 13 controls. A total of 532 genes were identified as differentially expressed. Those genes were involved in several functional groups, including myelination, ubiquitination, apoptosis and cell adhesion. In addition, several of those genes have been suggested to be involved in the development of other neural diseases. Expression profiling of the frontal cortex from seven cirrhotic alcoholics was conducted to examine how concomitant liver cirrhosis influences gene expression in human brain. Both glial and neuronal cells were affected at the transcriptional level in cirrhotic alcoholics relative to non-cirrhotic alcohol abusers. Gene expression profiling was also performed in alcoholic blood to identify potential biomarkers for alcohol abuse. Initial studies indicated that gene expression levels were also affected in the blood of alcoholics. In conclusion, a consistent re-programming of gene expression occurs in the brain of alcohol abusers with and without concomitant liver cirrhosis. Similar changes may also exist in the blood of alcoholics.