Regulation of Gene Expression

Many people drink alcoholic beverages, but relatively few of them become addicted to alcohol (alcoholic). Alcoholism is characterized by a compulsion to consume alcohol, tolerance (increasing doses are needed for the same effect), and dependence (abrupt cessation of consumption leads to severe withdrawal symptoms). In most alcoholics, alcohol provides pleasant sensations (positive reinforcement) and alleviates unpleasant ones such as anxiety (negative reinforcement).

Alcoholism is a complex disease. Psychologists sometimes speak of “addictive personalities,” and genetic studies indicate there may be inherited factors that predispose people to the disease. One approach to describing the genes involved is to study animal models of alcoholism at the molecular level. James Murphy at Indiana University has bred a genetic strain of alcoholic rats, called P rats, that prefer alcohol when given the choice of alcohol-containing or alcohol-free water. P rats show many of the symptoms of addiction, including compulsive drinking, tolerance, and withdrawal. These rats appear more anxious than wild-type rats, spending more time in a closed rather than an open environment. Drinking alcohol alters this behavior and seems to relieve their anxiety.

There may be a link between a particular protein and alcohol consumption. CREB (cyclic AMP response element binding protein) is abundant in the brain and regulates the expression of hundreds of genes that are important in metabolism. CREB becomes activated when it is phosphorylated by the enzyme protein kinase A, which in turn is activated by the second messenger cyclic AMP. In an effort to understand the molecular basis of alcoholism and anxiety, neuroscientist Subhash Pandey and his colleagues at the University of Illinois compared CREB levels in the brains of P rats and wild-type rats. They found that P rats have inherently lower levels of CREB in certain parts of the brain. When these rats consumed alcohol, the total levels of CREB did not increase, but the levels of phosphorylated CREB did. It is the phosphorylated version of CREB that regulates gene transcription.

The prospect that CREB, a molecule that regulates gene expression, is a key element in the genetic propensity for alcoholism is important because it begins to explain the molecular nature of a complex behavioral disease. Such understanding may permit more effective treatment of alcohol abuse, or even its prevention. And for our purpose here, it underscores the importance of the regulation of gene expression in biological processes.