Future Directions in Alcoholism Research
Alcohol affects the process by which genes direct the synthesis of proteins (i.e., expression). Therefore, patterns of gene expression in the presence of alcohol can help scientists identify the specific molecular sites of alcohol’s actions within the brain. New technologies can detect and quantify changes in the expression of thousands of genes simultaneously by scanning microscopic gene arrays applied to glass or silicon chips an inch or so square. However, genes whose activity is altered in the presence of alcohol may either be contributing to alcoholism development or may be reacting to alcohol’s presence. This question can be researched by observing the effects of manipulating the level of specific gene products. One way to accomplish this end is by means of viruses that have been engineered to express a specific gene in infected cells. This technique has been applied successfully in studying addictive behaviors. It is suggested that patterns of gene expression may become a diagnostic tool, with differen t disease states being characterized by distinct expression profiles. KEY WORDS: gene expression; protein synthesis; genome; virus; mRNA; hippocampus; ventral tegmental area; animal model
Polonged or repeated exposure to alcohol can lead to long-term changes in the function of nerve cells (i.e., neurons) within the brain. Researchers believe that these changes underlie certain manifestations of addictive behavior, such as tolerance, withdrawal, and the persistent craving for alcohol that appears to provoke relapse after prolonged abstinence. The molecular mechanisms underlying these long-term neurological changes largely involve specific brain proteins that play various roles in communication among neurons.
Information encoded in a cell’s genetic material directs the synthesis of a given protein. Thus, in whole organisms, the coordinated control of genes determines an individual’s basic structure. Minor variations among genes account for the normal range of inherited differences between individuals in a population. Conversely, major genetic variation may underlie an individual’s vulnerability to disease. At its most basic level, a dormant gene may become active in response to chemical messengers that signal a cell’s increased need for the gene’s particular protein product. The genetic information contained in the DNA is transcribed in the cell’s nucleus into a form that can be interpreted by the protein-synthesizing components of the cell called messenger RNA (mRNA). The process by which a gene changes its activity in directing the synthesis of its specific mRNA and the resulting protein is called expression.
Research indicates that alcohol affects gene expression (Bachtell et al. 1999). Furthermore, the pattern of gene expression in the presence of alcohol provides evidence for scientists to deduce the specific molecular sites of alcohol’s action within the brain (Miles 1995). This article focuses on two new approaches for analyzing gene expression that show potential for use in aspects of alcoholism research.
GENE EXPRESSION
Differential Expression
The differential expression approach detects and quantifies alterations in gene expression by indirectly measuring mRNA levels. Using this approach, Chen and colleagues (1997) studied differential expression in male rats after long-term (14-day) administration of alcohol. The investigators determined the total RNA content of specific brain regions. One significant difference detected in the alcohol-exposed rats was a striking elevation of a specific mRNA in the hippocampus that lasted up to 48 hours after withdrawal from alcohol (Chen et al. 1997). The hippocampus is involved in learning and memory and may play a role in alcohol-induced memory blackouts as well as seizures that often accompany the acute withdrawal syndrome following cessation of heavy drinking. The specific mRNA was determined to play a role in the synthesis of an enzyme crucial to energy metabolism in mitochondria. Mitochondria are structures within cells where most of the cell’s energy is produced. Based on these considerations, the results of the experiment of Chen and colleagues supports the idea that alcohol exposure causes defects in mitochondria that may also play a role in such health consequences as alcohol-induced liver disease.
In a comparison study of human brain tissue obtained post mortem from alcoholics and nonalcoholics, Fan and colleagues (1999) measured levels of different types of mRNA obtained from different brain regions. Levels of a specific mRNA were higher in the nucleus accumbens of alcoholic brains compared with nonalcoholic brains. This differentially expressed mRNA is known to play a role in the final stages of mitochondrial protein synthesis. The nucleus accumbens is a center of motivation and stress response and is implicated in the development of alcoholism. Taken together, these results are consistent with the possibility that alcohol-induced activation of energy metabolism in the nucleus accumbens plays a role in alcoholism development.