The Genetic Basis of Addiction
The Genetic Basis of Addiction
Genetic factors play a significant role in addiction. Epidemiological studies have long established that alcoholism, for example, is familial, with estimates that 40% to 60% of the risk for this disorder is genetic (Kendler et al., 2000; Reich et al., 1998; Tsuang et al., 1998). Other studies have suggested similar rates of heritability for other drug addictions, such as to opiates and cocaine (Kendler et al., 2000; Kendler and Prescott, 1998; Tsuang et al., 2001). Numerous genetic linkage and association studies are now underway to identify the specific genes that comprise this risk. While investigators have identified several relatively large chromosomal regions as being possibly involved, no specific genetic polymorphism has yet been tied to addiction vulnerability with certainty. The one exception is the genetic defects found in certain East Asian populations in enzymes (e.g., alcohol and aldehyde dehydrogenases) that metabolize alcohol (Chen et al., 1999). These defects dramatically increase side effects of acute alcohol intake, thereby reducing the individual's vulnerability to alcoholism.
It is well-established that inbred strains of mice and rats show robust differences in behavioral and biochemical responses to drugs of abuse (Berrettini et al., 1994; Brodkin et al., 1998; Crabbe et al., 1999; McBride and Li, 1998). In addition, lines of rodents have been selectively bred for alcohol (or other drug) responsiveness. While the genetic variations that occur in animal models may be different from those in humans, identification of genes will provide insight into mechanisms underlying the addiction process. No specific genetic polymorphism has yet been identified in these animal models.
The difficulty in finding genes that contribute to risk for addiction parallels the difficulty in finding genes for other psychiatric disorders and, in fact, for most common diseases. Among the many reasons for this difficulty is the fact that addiction is a complex trait with many genes possibly involved. Thus, any single gene might produce a relatively small effect and would, therefore, be difficult to detect experimentally. It is also possible that variants in different genes may contribute to addiction in each family or rodent model.
Of course, vulnerability to addiction is only partly genetic; nongenetic factors -- which may include stochastic or random events during development or a host of environmental factors throughout life -- are also important (Jacob et al., 2001). Such environmental factors remain only vaguely defined (e.g., poverty, crime, delinquency). In animals, environmental factors such as stress can interact with an animal's genotype to determine its ultimate responses to a drug of abuse. As a result, delineating the mechanisms by which specific genetic variations and specific environmental factors interact is an important focus of investigation.
A gene could contribute to addiction vulnerability in several ways. A mutant protein (or altered levels of a normal protein) could change the structure or functioning of specific brain circuits either during development or in adulthood. These altered brain circuits could change the responsiveness of the individual to initial drug exposure or the adaptations that occur in the brain after repeated drug exposure. Likewise, environmental stimuli could affect addiction vulnerability by influencing these same neural circuits. Perhaps combining genetic approaches with more narrowly defined phenotypes would facilitate the identification of addiction vulnerability genes.
Genetic Dissection of Behavior
In contrast to the difficulty in finding genetic factors that control individual risk for addiction, great strides have been made in demonstrating the role of specific gene products in the complex behavior of addiction as assessed in animal models. The general strategy is to modify the amount of a particular gene product, or in some cases to modify the product itself, and to characterize the consequences of such modifications in behavioral tests. The genetic approaches used most often are constitutive mutations in mice (knockouts and overexpressors); such mice continue to provide important insight into drug mechanisms. In more recent years, mice with inducible and tissue-specific mutations have been used increasingly to overcome some of the limitations of the first-generation mutants. Other genetic approaches include viral-mediated gene transfer, intracerebral infusions of antisense oligonucleotides and mutations in nonmammalian model organisms.
Behavioral Tests for Addiction
Animals with altered levels of a particular gene product in the brain are then subjected to a variety of behavioral tests to assess their responses to drugs of abuse (Nestler, 2000). The most widely used tests are measures of locomotor activity (most drugs of abuse increase activity in rodents when given acutely) and the progressive increase in locomotor activity (locomotor sensitization) that occurs with repeated drug exposure. While the relationship between locomotor responses and drug reward and addiction remains a matter of some debate, locomotor responses are mediated by the mesolimbic dopamine system, which is also implicated in reward and addiction.
A more direct measure of drug reward is conditioned place preference, where an animal learns to prefer an environment that was paired with drug exposure. Conditioned place preference is also mediated partly by the mesolimbic dopamine system and is thought to model some of the powerful conditioning effects of drugs that are seen in humans. Place-conditioning assays, like measures of locomotor activity, are amenable to relatively high throughput, which explains their wide use. However, neither test directly measures the behavioral abnormalities (i.e., compulsive drug-seeking and drug-taking) that are the core features of human addiction.
To get closer to such abnormalities, operant tests must be used. In self-administration tests, animals work (press a lever) to give themselves an intravenous or oral dose of a drug of abuse. The paradigm can also be used to study incentive motivation for drug and relapse after a period of abstinence. In intracranial self-stimulation, animals work to electrically stimulate a particular brain area (e.g., mesolimbic dopamine system). This test is thought to measure the affective state of an animal and the sensitivity of brain reward pathways to drugs of abuse. In conditioned reinforcement, animals work to obtain a previously neutral conditioned stimulus (e.g., light) that has been paired with a natural reinforcer (e.g., water). Drugs of abuse potently stimulate incentive motivation for the conditioned reinforcer. However, these tests generally are far more complicated to perform, particularly in mice. Thus, to date, the tests have been applied to only a small number of genetically altered animals. A major challenge for the field is to devise schemes that make application of these behavioral tests more widely available.
Confirming Initial Drug Targets
One of the most straightforward ways that genetic tools have been used in the addiction field is to confirm the initial protein target for a drug of abuse. While classic pharmacological approaches have revealed many initial drug targets, they often have failed, for example, to identify which of several receptor subtypes is most important. In this way, tests of knockout mice lacking the opioid receptor, dopamine transporter, CB1 cannabinoid receptor or ß2 nicotinic acetylcholine receptor have confirmed that these are the initial targets that mediate the acute rewarding and other effects of opiates, stimulants, cannabinoids or nicotine, respectively.