The processes of alcohol tolerance and dependence - Special Focus: Alcohol and the Brain

Alcohol Health & Research World, Spring, 1990 by R. Adron Harris, Karl J. Buck

Another class of medications that shows promise for the treatment of alcohol dependence are the serotonin uptake inhibitors, originally developed to treat depression. (Serotonin is an important neurotransmitter in the brain and is thought to be involved in depression, appetite control, and other responses.) These compounds inhibit the uptake of serotonin at the nerve ending, making more of it available in the synapse. One of these compounds, fluoxetine (Prozac), reduces alcohol consumption in both rats and humans (McBride et al. 1988). (See the article by Liebowitz et al., pp. 144-153).

GENETICS OF TOLERANCE AND

DEPENDENCE

Tolerance

Animals tend to increase their alcohol consumption as a function of exposure in various alcohol self-administration tests, suggesting the development of tolerance. More substantive evidence suggesting a link between alcohol preference and tolerance is provided by genetic studies showing correlations between alcohol preference and the development of tolerance in animals selected for differences in voluntary alcohol intake. Alcohol tolerance develops more rapidly and persists longer in the alcohol-preferring (P) than in the alcohol-nonpreferring (NP) lines of rats (Li et al. 1987). Earlier studies also showed a positive correlation between initial sensitivity to alcohol and the development of alcohol preference and tolerance (Nikander and Pekkanen 1977; Schneider 1973). These approaches are being used in several laboratories to attempt to learn whether genetic differences in alcohol consumption are caused by genetic differences in tolerance development.

Dependence

Genetic selection has resulted in lines of animals that differ greatly in their susceptibility to withdrawal seizures, and, presumably, in the degree of alcohol dependence that develops. These Withdrawal Seizure Prone (WSP) and Withdrawal Seizure Resistant (WSR) lines of mice show very different intensities of withdrawal signs despite equal blood levels of alcohol during chronic alcohol treatment (Phillips et al. 1989). However, these lines do not differ in the development of tolerance to alcohol hypothermia (Phillips et al. 1989).

These data suggest that tolerance and dependence are controlled by different sets of genes. However, they do not rule out a common mechanism that may be responsible for some aspects of both tolerance and dependence. The selection of the WSP and WSR lines of mice shows that physical dependence clearly has a genetic component.

In addition, High Alcohol-Drinking and Low Alcohol-drinking lines of rats have been selected (Phillips et al. 1989). The high alcohol-drinking lines will voluntarily consume rather large amounts of alcohol, whereas the low alcohol-drinking lines avoid consuming alcohol. Thus, two aspects of alcoholism, voluntary consumption and physical dependence, are under genetic control and can be demonstrated in laboratory animals.

There also is an extensive clinical literature demonstrating that alcoholism in humans has a strong genetic component (Devor and Cloninger 1989). Review of this literature is well beyond the scope of this article, but genetic studies do indicate that (1) something is inherited that causes predisposition to alcoholism in humans, and (2) a genetic factor causes development of alcohol dependence and alcohol drinking in laboratory animals (see the article by O'Conner et al., pp. 90-97). The key question is, What is inherited? The explosive development of molecular biology during the past few years provides tools to explore these questions in laboratory animals and potentially in humans. Laboratory animals provide a great opportunity to understand exactly which genes are required for development of dependence and for drinking of alcohol, and to determine whether these same genes play a role in the development of alcoholism. Such studies are currently underway in several laboratories.