Genes associated with alcohol abuse and tobacco smoking in the human nucleus accumbens and ventral tegmental area.

Background: The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown, but interactions between these drugs have important implications for the development of and recovery from drug dependence.

Methods: We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the 2 behaviors on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity. Changes in gene expression were established by factorial ANOVA. Unsupervised hierarchical clustering was utilized to probe the strength of the data sets. Applying real-time PCR differential expression of candidate genes was confirmed in the nucleus accumbens and explored further in a second core region of the mesolimbic system, the ventral tegmental area.

Results: Subjecting the data sets derived from microarray gene expression screening to unsupervised hierarchical clustering tied the cases into distinct groups. When considering all alcohol-responsive genes, alcoholics were separated from nonalcoholics with the exception of 1 control case. All smokers were distinguished from nonsmokers based on similarity in expression of smoking-sensitive genes. In the nucleus accumbens, alcohol-responsive genes were associated with transcription, lipid metabolism, and signaling. Smoking-sensitive genes were predominantly assigned to functional groups concerned with RNA processing and the endoplasmic reticulum. Both drugs influenced the expression of genes involved in matrix remodeling, proliferation, and cell morphogenesis. Additionally, a gene set encoding proteins involved in the canonical pathway "regulation of the actin cytoskeleton" was induced in response to alcohol and tobacco co-abuse and included. Alcohol abuse elevated the expression of candidate genes in this pathway in the nucleus accumbens and ventral tegmental area, while smoking comorbidity blunted this induction in the ventral tegmental area.

Conclusions: The region-specific modulation of alcohol-sensitive gene expression by smoking may have important consequences for alcohol-induced aberrations within the mesolimbic dopaminergic system.