VULNERABILITIES TO ADDICTION

In this brief chapter it is not possible to address all the reasons why some individuals who use addictive drugs become dependent and others do not, and why some stop using and others do not. Risk factors for becoming addicted are as yet poorly understood but can be divided into factors that increase consumption and factors that increase the likelihood that the individual will be captured by the drug. Both genetic and environmental factors likely influence both the willingness of an individual to experiment with drugs and alcohol as well as the risk of developing dependence.

There is very little known currently about potential genetic contributions to vulnerability to opiate, cocaine, or nicotine addiction. However, most researchers agree, based on three types of investigations, that there are clear genetic components to vulnerability to alcoholism. These investigations are twin and adoption studies, genetic studies of certain human populations, and animal studies. Twin and adoption studies have demonstrated that early onset alcoholism is strongly influenced in males and females by genetic factors. Later onset alcoholism seems less influenced by genetic factors and more strongly influenced by environmental and emotional factors (Cloninger et al., 1989; Heath et al., 1991a,b; Kendler et al., 1992).

Genetic studies have focused on individuals in populations in which many people exhibit a strong aversive physiological reaction to alcohol (alcohol flush reaction), which is sometimes inaccurately called an allergy to alcohol. It includes facial flushing, rapid heartbeat, and headaches. The alcohol flush reaction, which if severe enough can cause loss of consciousness, occurs in roughly half of people with Chinese and Japanese ancestry and about a third of people with Korean ancestry. The flush reaction may represent a physiological "protective" factor that tends to prevent affected individuals from developing an alcohol addiction. The biological basis of this flush reaction is a variation in two genes that code for two principal enzymes of alcohol metabolism, alcohol dehydrogenase (ADH) and an aldehyde dehydrogenase (ALDH2) located in a specific part of cells called mitochondria (Thomasson et al., 1991). The most alcohol-sensitive individuals in these populations are those who inherit from both parents (homozygous) the gene variant that causes ALDH2 deficiency; these individuals cannot drink even small amounts of alcohol. If only one such gene is inherited (heterozygous), the individual can drink but is less able to drink large quantities and is 4-6 times less likely to become addicted. Individuals with the variant gene for ADH are also less likely to become addicted, but the effect is not as great. Interestingly, Caucasians, Alaskan Natives, and Native American populations exhibit very low prevalence rates for these genetic variations (Thomasson et al., 1994).

Genetic vulnerability to alcohol addiction can also be studied in animal models, including rats, mice, and even fruit flies (see Appendix D). Several rat strains have been developed through selective breeding that exhibit high or low



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