Alcohol dependence, withdrawal, and relapse

Abstract

Continued excessive alcohol consumption can lead to the development of dependence that is associated with a withdrawal syndrome when alcohol consumption is ceased or substantially reduced. This syndrome comprises physical signs as well as psychological symptoms that contribute to distress and psychological discomfort. For some people the fear of withdrawal symptoms may help perpetuate alcohol abuse; moreover, the presence of withdrawal symptoms may contribute to relapse after periods of abstinence. Withdrawal and relapse have been studied in both humans and animal models of alcoholism. Clinical studies demonstrated that alcohol-dependent people are more sensitive to relapse-provoking cues and stimuli than nondependent people, and similar observations have been made in animal models of alcohol dependence, withdrawal, and relapse. One factor contributing to relapse is withdrawal-related anxiety, which likely reflects adaptive changes in the brain in response to continued alcohol exposure. These changes affect, for example, the body's stress response system. The relationship between withdrawal, stress, and relapse also has implications for the treatment of alcoholic patients. Interestingly, animals with a history of alcohol dependence are more sensitive to certain medications that impact relapse-like behavior than animals without such a history, suggesting that it may be possible to develop medications that specifically target excessive, uncontrollable alcohol consumption.

Figure 1

Schematic illustration of how problem drinking can lead to the development of dependence, repeated withdrawal experiences, and enhanced vulnerability to relapse. Alcohol dependence is characterized by fundamental changes in the brain’s reward and stress systems that manifest as withdrawal symptoms when alcohol consumption is stopped or substantially reduced. These changes also are purported to fuel motivation to reengage in excessive drinking behavior. Repeated bouts of heavy drinking interspersed with attempts at abstinence (i.e., withdrawal) may result in sensitization of withdrawal symptoms, especially symptoms that contribute to a negative emotional state. This, in turn, can lead to enhanced vulnerability to relapse as well as favor perpetuation of excessive drinking.

Figure 2

Enhanced voluntary alcohol drinking in dependent mice produced brain alcohol concentrations similar to those achieved during the chronic alcohol exposure that initially rendered the animals dependent. Samples were collected from the nucleus accumbens of alcohol-dependent mice that had undergone three cycles of chronic intermittent alcohol vapor exposure (red symbols) and nondependent controls (black symbols). Samples were taken before, during, and after the 2-hour drinking session, when the mice had the opportunity to voluntarily drink alcohol (15 percent vol/vol) or water. Alcohol intake during the drinking session was 3.04 ± 0.15 g/kg for dependent mice and 2.32 ± 0.28 g/kg for nondependent mice. The red bar indicates the 2-hour drinking session. Horizontal lines and shaded area represent brain alcohol levels (means ± SEM) measured in the dependent mice during chronic intermittent alcohol exposure (28.4 ± 3.5 mM). NOTE: Brain alcohol concentrations (mM) were measured in microdialysis samples collected from the nucleus accumbens. Values are corrected for calculated recovery rates (∼10 percent) for microdialysis probes. SEM = standard error of the mean. SOURCE: Data are adapted from Griffin et al. 2008.