Alcohol's Effects on Gene Expression.

Chronic heavy drinkers can tolerate alcohol without exhibiting obvious signs of impairment at doses that in other people would be incapacitating or even fatal. For example, in nonalcoholic people, blood alcohol concentrations (BAC's) of 0.6 percent and more usually cause death from respiratory failure. Chronic heavy drinkers, in contrast, frequently survive similar alcohol doses and may even appear sober (Charness et al. 1989). This acquired resistance to the effects of high alcohol doses is called tolerance and is one of the criteria used to establish a medical diagnosis of alcohol dependence (American Psychiatric Association 1994). The development of tolerance indicates that the brain has adapted to the chronic presence of alcohol. As a consequence of this adaptation, the brains of many alcoholics need elevated alcohol levels to function normally. Conversely, drinking cessation leads to adverse effects in the form of withdrawal symptoms. This state is known as physical dependence. The mechanisms underlying the phenomena of tolerance and dependence are currently unknown. Increased metabolism of alcohol does not explain why alcoholics' brains function differently from those of nontolerant people in the presence of equal alcohol concentrations. The time course for the development of tolerance and dependence does, however, suggest a general hypothesis: Changes in the expression of specific genes may account for at least some of the dramatic changes evident in chronic heavy drinkers' brain functions. Behavioral studies in both humans and animals have found that tolerance and physical dependence can develop over several days of chronic alcohol exposure. Such a timeframe is consistent with the duration required to induce changes in gene expression in response to alcohol exposure. The term "changes in gene expression" refers to increases or decreases in the amount of gene products (i.e., proteins) synthesized from specific genes.(1) Other regulatory events in the cells, such as activating or deactivating proteins by adding or deleting phosphate groups, occur much more rapidly, that is, within minutes. Conversely, some changes that have been observed after chronic alcohol exposure, such as the "rewiring" of nerve cell connections or decreases in the number of brain cells, occur too slowly to explain the full range of events seen with tolerance and dependence in alcoholics. Over the past few years, a number of researchers have identified several genes whose expression is modified after exposure of animals or of cells in tissue culture to alcohol. For some of these genes, expression is increased (Charness et al. 1988; Gayer et al. 1991; Miles et al. 1991), whereas for other genes, expression is decreased (Mochly-Rosen et al. 1988; Morrow et al. 1990). This article briefly describes the identification of alcohol-responsive genes and their possible physiological roles in the body's response to alcohol. Finally, this article presents possible mechanisms through which alcohol may regulate gene expression. IDENTIFYING ALCOHOL-REGULATED GENES To identify genes whose expression in the brain is altered after alcohol exposure, researchers employ several strategies. As starting material, they generally use nerve cells grown and incubated with alcohol in tissue culture or tissue from animals exposed to alcohol. Once a model system is chosen, different technical approaches can be used to characterize the alcohol-responsive genes. Two such approaches are briefly described below. Study of Candidate Genes The most straightforward approach to identifying alcohol-regulated genes is to study genes that already have been isolated and that are known or suspected to contribute to alcohol's effects on the body. Such genes are called candidate genes. By comparing protein production of the candidate genes in cells that have or have not been exposed to alcohol, researchers can determine whether alcohol increases, decreases, or has no effect on the genes' expression. …