Addiction

Addiction in its broadest sense can be defined as the habituation to a practice considered harmful. A more narrow definition of the term refers to chronic use of a chemical substance in spite of severe psychosocial consequences. Terms such as "workaholic," "sex addict," and "computer junkie" arose to describe behaviors that have features in common with alcoholism and other substance addictions. The most convincing data supporting a role of genetics in addiction has been collected for alcoholism, although genetics most likely has a role in other forms of addiction.

Definitions

In order to assess alcoholism, or any form of addiction, a clear definition of the condition is necessary. The American Psychiatric Association and the World Health Organization have developed clinical criteria (DSM-IV and ICD10, respectively) that are widely used for the diagnosis of substance-use related disorders. DSM-IV criteria recognizes ten classes of substances (alcohol, amphetamines, cannabis, hallucinogens, inhalants, nicotine, opioids, phencyclidine, and sedatives) that lead to substance dependence, another term for addiction.

The precise diagnostic criteria for dependence vary among substances. DSM-IV defines dependence as manifesting, within a twelve-month period, at least three of the following criteria:

Tolerance (increased dose needed to achieve the same affect, or reduced response to the same dose)
Withdrawal symptoms
Progressive increase in dose or time used
Persistent desire for, or failure to reduce substance use
Increasing efforts made to obtain substance
Social, occupational, or recreational activity is replaced by activity associated with substance use
Continued substance use despite recognized physical and psychological consequences

Heritability in Humans

Most family, twin, and adoption studies have shown that addiction to alcohol has significant heritability. For example, there is an increased risk for alcoholism in the relatives of alcoholics. Depending on the study, the risk of alcoholism in siblings of alcoholics is between 1.5 and 4 times the risk for the general population. The identical twins of alcoholics (who share 100 percent of their genes) are more likely to be alcoholics than the fraternal twins of alcoholics (who share only about 50 percent). Adoption study data suggest that the risk for developing alcoholism for adopted children is influenced more by whether their biological parents were alcoholics than whether their adopted parents are alcoholics, suggesting that genes contribute to alcoholism more than environment. Similar but less extensive data has been collected for nicotine addiction. Very little genetic epidemiological data has been collected for illegal drugs.

The only genes that have been conclusively shown to affect susceptibility to addiction in humans are genes that encode proteins responsible for the metabolism of alcohol. In the body, ethanol ("drinking" alchohol) is oxidized by enzymes to acetaldehyde and then to acetate. Certain alleles of aldehyde dehydrogenase genes that are common in some populations, such as Asians, lead to increased levels of acetaldehyde when alcohol is consumed. Acetaldehyde causes an unpleasant flushing reaction that leads to a voluntary reduction of alcohol consumption. The systematic search for other genes that affect susceptibility to alcohol and nicotine addiction in humans has lead to the identification of chromosome loci that may contain genes that affect susceptibility to addiction, but has not lead to the identification of any specific genes.

Models of Addiction

Progress in genetic analysis of addiction in animal models has been more successful. The pharmacologic effects of abused substances can readily be demonstrated in many model systems, from worms to rodents. Rodents can be trained to voluntarily consume alcohol and other abused substances. Once trained, these rodents will expend energy to continue to receive drugs and will display withdrawal symptoms when denied drugs. Chromosomal regions with naturally occurring variants that affect voluntary consumption, intoxication, and withdrawal have been mapped in mice. The specific genes responsible for these effects have not yet been identified.

Cell biology and neurochemistry studies in humans and model systems have identified many molecules that have altered abundance and distribution, enzymes with altered activity, and genes with altered expression resulting from substance abuse. In particular, the dopamine and serotonin neurotransmitter systems have been the focus of intense studies. These are brain systems directly involved in many basic responses, including pleasure and reward systems.

To directly test the role of specific genes and pathways, mice have been engineered to delete or over-express genes. Mice lacking any of these genes (called PKC_ε, DRD2, and DBH) are more sensitive to the effects of alcohol and consume less alcohol. In contrast, mice lacking any one of four other genes (PKA regulatory II_β, NPY, or 5-HT_1b) are less sensitive to the effects of alcohol and consume more alcohol. Mice cannot be trained to self-administer alcohol if they lack the Mu opioid receptor, which is involved in transmitting signals to the body's own internal opiate system.

Mutant fruit flies with altered responses to alcohol intoxication have also been created. Two mutants, called "cheapdate" and "amnesiac," arise from different mutations in the same gene. These mutations affect the cellular level of the signal transduction molecule cyclic-AMP. As the names imply, flies with cheapdate mutations are very sensitive to the affects of alcohol, and flies with amnesiac mutations are unable to learn.

The major conclusion from work in model systems is that the pathways and systems involved in addiction are central to normal behaviors with instinctive reward processes, such as feeding and procreation. Addiction is a process that involves learning and the subversion of these basic reward pathways.

Kirk C. Wilhelmsen

Bibliography

American Psychiatric Association Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.

Begleiter, Henri, and Benjamin Kissan, eds. The Genetics of Alcoholism. New York: Oxford University Press, 1995.

Tamara J. Phillips, et al. "Alcohol Preference and Sensitivity Are Markedly Reduced in Mice Lacking Dopamine D2 Receptors." Nature Neuroscience 1 (1998): 610-615.

Theile, Todd, et al. "Ethanol Consumption and Resistance Are Inversely Related to Neuropeptide Y Levels." Nature 396 (1998): 366-369.

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