Molecular actions of alcohol and smoking on the drug reward pathway of the brain By Dr Traute Flatscher-Bader

Alcoholism is a multifactorial disease with genetic and environmental risk components. My work on differential transcription in the mesolimbic system, (the addiction pathway) of the human brain, generated a database of alcohol- and smoking–sensitive gene sets. Some of these genes encode proteins involved in rearrangement of nerve connections. I propose that changes to the expression of these genes are important for the development or maintenance of drug addiction. Additionally, large databases of candidate genes for predisposition to alcohol and nicotine addiction have recently become available following genome wide screens. In an initial comparative analysis I identified a number of genes common to these databases.

This study aimed to investigate further the expression of a selection of candidate genes in distinct regions of the human reward pathway.

34 candidate genes were selected. To confirm differential expression of these genes postmortem brain tissue was utilized of a large set of well characterised alcoholics and smokers, co-abusers and control cases obtained from the NSW Tissue Resource Centre. Applying PCR technology the expression levels of the genes within core regions of the mesolimbic system was established. Western blots and immunohistochemistry were preformed on a subset of the candidate genes to quantify and localise changes in protein expression within the target brain regions.

17 of the candidate genes were confirmed as sensitive to alcoholism and / or smoking. The differential expression of most of these genes was region and / or drug-specific. However, notable was a set of genes, which was induced by alcoholism in two brain regions. This may reflect common and region-specific aspects in the action of the two drugs. The majority of the identified drug-sensitive genes are involved in pathways associated with cellular remodeling and included an alcohol-sensitive gene with a crucial role in regulation of neuronal cell shape and plasticity. Additionally, a gene important to excitatory neurotransmission was differentially expressed in both, alcoholics and smokers. I concluded that structural plasticity and alterations to excitatory neurotransmission may contribute to the development or maintenance of human alcohol addiction. The results of this study are currently prepared for publication.