Proteomic analysis of neurodegeneration in the alcoholic brain
The incidence of co-abuse of alcohol and tobacco is as high as 80–90% and the interactions between the drugs have important implications for the development of, and recovery from, drug dependence. However, the molecular mechanism underlying this comorbidity is virtually unknown. To investigate the effects of smoking and alcohol consumption, and the interaction of the two behaviours, on the gene expression in the human nucleus accumbens (NA), the expression profile of 20 alcoholic and control cases, with and without smoking comorbidity, was determined using cDNA microarrays. The data was analysed using one- and two-way ANOVA and hierarchical gene clusters. Gene sets were annotated, grouped and mapped to canonical (KEGG) pathways using DAVID software (http://david.abcc.ncifcrf.gov/). The significance of functional enrichment scores was determined using kappa statistics. Differential expression of a smoking-sensitive gene set clustered all smoking cases, irrespective of alcohol exposure, and predicted smoking comorbidity in alcoholics. An alcohol-sensitive gene set was less dominant and did not distinguish alcohol abuse in the chronic smoker. Smoking-sensitive genes were predominantly assigned to functional groups encoding proteins involved in regulation of transcription, RNA metabolism and the mitogen-activated protein (MAP) kinase signalling pathway. Alcohol-sensitive genes were assigned to functional clusters associated with protein and RNA turnover and stress responses. One small but prominent alcohol-sensitive gene set encoding proteins involved in regulation of the actin cytoskeleton and focal adhesion. The two drugs interacted to influence expression of clusters of genes involved in signalling (including MAP kinase) and brain-specifi c functions such as neuron development, morphogenesis, axonogenesis or nerve ensheathment. We conclude that comorbidity may have a profound impact on plasticity within the NA and particularly alter structural connectivity. Further, our data indicate that smoking plays a dominant role in inducing these changes.