What is the relationship between genetics and substance abuse?

Genetic Evidence

The response of the human body to specific chemicals has long been known to have a genetic basis. In general, these effects can be considered to fall within two themes: in the presence of receptors on the cell surface that can be activated following the binding of a chemical and in the regulation of a metabolic pathway through the mechanism of chemical activation of specific enzymes. This is particularly true when applied to brain chemistry.

The functions of specific regions within the brain, including those that could include pleasure centers or those that control other forms of reactions to specific drugs, are subject to hereditary control. The expression of cell receptors and the production of enzymes that control pathways in the brain, each regulating the ability to respond to drugs, have an underlying genetic control.

Historically, the treatment of substance abuse, including that involving alcohol and drug addictions (both legal and illegal) has centered primarily on the moral or behavioral aspects of the problem. Treatment once believed that the addicted person has made a choice, first to use the substance and then to continue its use until addiction removes any personal control. While there is certainly a behavioral component involved—the initial use of the substance is affected by voluntary action and environmental factors—increasing evidence suggests a genetic predisposition to the addiction that may follow.

Most historical studies that have attempted to establish a genetic basis for addiction have utilized twin studies. These studies involve a comparison between twins, ideally living separate lives so as to avoid environmental influences in the study, in which the prevalence of substance abuse and addiction may be compared. Numerous epidemiological studies of twins have shown a significantly increased level of risk, even in the absence of environmental influences: If one twin developed an addiction, the other also demonstrated a significantly higher level of risk of doing so.

Adoption studies have reinforced the conclusions reached through twin studies. If a birth parent exhibited problems in the use of alcohol, then the child demonstrated significantly increased risk in exhibiting the same behaviors. However, if the child was adopted and thus did not share genetic features with the adoptive parent, the child exhibited no increased risk. Similar results also were found in cases of drug addiction.

The development of biochemical methods for studying brain chemistry and regulation of pleasure pathways has provided a means to investigate addiction at the molecular level. Studies have shown that some forms of addiction may be exacerbated by the expression of specific genes or pathways in the brain, which are controlled by the drugs in question. Another challenge in attempting to sort out what genes might be involved in addiction is that, often, no single gene is always involved. Rather, the interaction of a variety of genes, and in some cases metabolic pathways in the brain, contributes to addiction.

Genetics of Alcohol Addiction

Though the evidence is largely anecdotal, there is some indication that alcoholism may at some level be subject to genetic factors. It is known that alcoholism frequently repeats through family generations. As noted, studies of twins and comparisons between adoptive or biological children, in which a parent exhibits alcohol problems, support the argument for a genetic component to alcohol addiction. It remains unclear if alcoholism is primarily genetic or whether tendencies to addiction reflect the environment in which the person is raised. Experts agree that alcoholism may result from a combination of factors.

Supporting the argument that genetics may play a role in alcoholism was the discovery of a genetic link between a specific gene that encodes alcohol addiction and a molecule called the cyclic AMP responsive element binding protein (CREB). The CREB gene plays a role in the regulation of brain function during development; in particular, it has an association with the portion of the brain known as the amygdala. The scientific evidence for the role of the CREB gene supports what is known about the function of the amygdala, the region in the central brain that determines a portion of the body’s response to emotional disorders and stress.

Persons subject to alcoholism frequently have abnormal reactions to stress, a problem that may be ameliorated by alcohol. Depression and other abnormal responses to stress seem to reflect abnormalities in signaling patterns and gene expression within the amygdala. These abnormalities in turn seem to be caused by improper CREB protein regulation. Alcohol appears to reverse this process. In the presence of increased levels of alcohol, the CREB protein becomes functional, activates the signals within the amygdala, and alleviates the effects of stress. Reduced levels of the CREB protein in the amygdala exacerbates the anxiety levels of the subject, which then increases the subject’s desire (and need) for alcohol.

While most of these studies have been carried out in nonhuman animals, many of the identical physiological changes that occur in the brains of test animals, such as rats and mice, have identical counterparts in the human brain and its response to alcohol. Among the questions that should be addressed is whether the need for alcohol forms the basis for its addiction or whether the long-term abuse of alcohol results in the changes found within the brain.

Genetics and Stimulants

Stimulants such as cocaine, amphetamines (for example, methylene-dioxymethamphetamine, or ecstasy), and even tobacco and caffeine, seem to have in common the ability to utilize common mechanisms within the brain. One mechanism in particular on which addiction studies have focused is the regulation of certain neurotransmitters, chemicals released by neurons in the brain that act to stimulate nerve endings on adjacent nerve cells.

Neurotransmitters such as dopamine
, long known for its association with Parkinson’s disease, control neural pathways in the portion of the brain known as the striatum, the portion of the forebrain that controls emotions such as pleasure and certain behaviors. Stimulants such as cocaine or amphetamines increase the level of dopamine—cocaine by inhibiting the reuptake of dopamine and amphetamines by increasing their release. Regardless of their mechanism, stimulants cause drug-induced highs.

Studies in mice that have attempted to identify those genes that are particularly sensitive to the presence of stimulants have identified one gene that seems to play a common role: the post-synaptic density-95 (PSD-95) gene. The product of PSD-95 appears to function in regulating the structure of the receptor that serves as the target for dopamine in the pleasure centers of the striatum. Reduced levels of the PSD-95 protein in mice led to an increased response following exposure to cocaine. The sensitivity of mice to cocaine appears to correlate with the level of the PSD-95 protein.

Because most stimulants, including tobacco and alcohol, likewise act in part by increasing the level of dopamine within the striatum, the PSD-95 protein may represent a common feature in the response to the presence of these drugs. Genetic variation in the activity of the PSD-95 gene may be one of the determining factors in both the behavioral response in using stimulants and in the likelihood the user may ultimately become addicted.

Bibliography

"Family History and Genetics." National Council on Alcoholism and Drug Dependence. NCADD, 25 Apr. 2015. Web. 29 Oct. 2015.

Kendler, Kenneth, and Carol Prescott. Genes, Environment, and Psychopathology: Understanding the Causes of Psychiatric and Substance Use Disorders. New York: Guilford, 2007. Print.

Kipper, David, and Steven Whitney. The Addiction Solution: Unraveling the Mysteries of Addiction through Cutting-Edge Brain Science. New York: Rodale, 2010. Print.

Miller, William, and Kathleen Carroll. Rethinking Substance Abuse. New York: Guilford, 2006. Print.

Wand, Gary. “The Anxious Amygdala: CREB Signaling and Predisposition to Anxiety and Alcoholism.” Journal of Clinical Investigation 115 (2005): 2697–99. Print.