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

The Processes of Alcohol Tolerance and Dependence

Abuse, occasional use, and even therapeutic use of many drugs may lead to the development of tolerance and dependence. Tolerance for and dependence on alcohol and other drugs promote drug intake, increasing the damaging effects of the drug over time. This article provides an overview of what is known about the processes of tolerance and dependence, and discusses rescent scientific developments that reveal more about these phenomena. For a more detailed review of alcohol tolerance and dependence, several excellent reviews are available (Goldstein 1983; Koob and Bloom 1988; Kalant et al. 1971).

ALCOHOL TOLERANCE

Tolerance means that more of a drug is required to achieve an effect. Tolerance to alcohol can be demonstrated in two ways. First, the effect of a given dose of alcohol decreases as tolerance develops. Second, a greater dose of alcohol is required to produce a given effect. People may become tolerant to the desired effects of alcohol as well as to its aversive (unpleasant) effects. Tolerance can develop after a period of chronic alcohol exposure (protracted tolerance) or after a single dose (acute tolerance). It also can be expressed as strong individual and animal strain differences in initial sensitivity to alcohol (innate tolerance). Tolerance can be studied behaviorally in animals and humans, or biochemically in isolated organs, brain cells, and membranes. The use of isolated cells and other simple systems allows the investigation of the mechanism of tolerance at a molecular and genetic level.

The development of tolerance allows and encourages increased intake of alcohol because more of the drug is required to achieve the same effect. There are several consequences of tolerance. The first is that higher blood levels of alcohol, maintained for longer periods of time, result in increased damage to many organ systems. Particularly vulnerable are the stomach, where bleeding occurs, and the liver, where fat deposition and cirrhosis occur. In addition, chronic alcohol consumption results in increased alcohol metabolism, as explained below. The metabolism of alcohol upsets the energy balance of the cell and results in altered metabolism of hormones and other compounds by the liver.

Tolerance to alcohol also results in cross-tolerance, decreasing the effectiveness of other sedatives such as benzodiazepines and barbiturates. Therefore, alcoholics undergoing withdrawal may require very large doses of benzodiazepines to produce sedation. In one case, benzodiazepine dosages hundreds of times larger than normal (2,335 mg diazepam administered intravenously plus 21,225 mg oxazepam administered orally) were required to reduce agitation in an abstinent alcoholic (Woo and Greenblatt 1979). People do not become tolerant to all the effects of alcohol at the same rate. Tolerance to the different effects of alcohol develops differentially, varying in extent, persistence, tolerance develops more to the aversive effects than to the rewarding effects. For example, initial exposure to alcohol is associated with sedation and depression; there is evidence that with continued use, these side effects dissipate while the activating or pleasurable effects persist (Kiianmaa and Tabakoff 1982). Sedatives such as alcohol and barbiturates are particularly dangerous in this regard, because tolerance does not develop readily to toxic effects, such as respiratory depression and lowering of body temperature (hypothermia) (Jaffe 1985). Thus, a person may continue to take increasing amounts of a sedative without experiencing aversive effects, finally achieving drug levels that produce toxicity. In addition, tolerance does not develop to some injurious effects such as liver damage. One form of tolerance, metabolic tolerance, can increase tissue damage resulting from chronic alcohol use, as discussed below.

Mechanisms of Alcohol Tolerance

Metabolic Tolerance. Alcohol is metabolized almost entirely in the liver, where the enzyme alcohol dehydrogenase (ADH) oxidizes alcohol to form acetaldehyde. Alcohol also can be oxidized by the liver enzyme catalase and by an enzyme complex known as the microsomal ethanol-oxidizing system (MEOS). Chronic alcohol consumption increases the amount of these liver enzymes, a process known as enzyme induction (Kalant et al. 1971; Lieber et al. 1975a, b; Videla and Israel 1970). As a result, there is a small increase in the ability of the liver to metabolize alcohol in alcohol-tolerant subjects, so that a larger dose of alcohol is needed to achieve the same blood and brain alcohol levels. However, the increase in alcohol oxidation in alcohol-tolerant subjects is limited and can account only partially for alcohol tolerance.

Enzyme induction in alcohol-tolerant subjects also is important because these enzymes normally metabolize hormones in the body, and also metabolize drugs other than alcohol. Thus, induction of these enzymes nparticularly cytochrome P450, a component of MEOS) leads to hormonal imbalances and also can alter the effects of drugs taken concomitantly. For example, enzyme induction increases the rate of testosterone metabolism in males, thus causing low testosterone levels in alcoholics. The cytochrome P450 enzyme system also is responsible for metabolism of medications such as barbiturates. Enzyme induction by alcohol can increase clearance of these substances from the body, resulting in metabolic cross-tolerance to barbiturates and other drugs.