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The promise of genetic research

July 15, 2011
by Barbara Hesselgrave
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The field moves closer to predicting which treatments will work for specific clients

For many people, the troubling question “Why can't you just quit?” elicits a frustrated reply: “I've tried-it's just beyond my control!” Much criticized as volitional weakness, this statement increasingly is being seen as closer to the truth when examined under the light of new investigations.

Treating a disease such as addiction by looking at its fundamental physiological cause, rather than its symptoms, represents an emerging shift in approach being fueled by ever-expanding resources and discoveries in genetics and molecular biology.

Translating genetic discoveries into practice is already advancing new paradigms of patient care in other branches of healthcare, bringing the medical community closer to individualized treatments and better outcomes. Genomic testing being conducted in oncology and immunology, for example, is helping clinicians to predict, to diagnose, and to select therapies based on an individual's unique genetic blueprint. As the epidemiology of addiction unfolds, the field is learning more about how genetics can affect behavior. Arenas of new research offer promising evidence that is likely to shift treatment and to advance development of novel, targeted medication therapies.

David Shurtleff, PhD, acting deputy director of the National Institute on Drug Abuse (NIDA), says his agency is the major funding source worldwide for scientists to explore genetics' role in addiction. Shurtleff says research is “just scratching the surface of what we know” about the role genes play.

“We're learning that addiction is a dynamic process that starts with initiation-which for many is where it ends,” says Shurtleff. But for relapsing drug users and alcoholics with acute withdrawal, “There are really three major factors: genes, environment and development, that contribute to the disease.”

Explaining adolescent behavior

Often criticized for their unwise behaviors, teens engage in impetuous thinking that does have a physiological basis, and this plays an early role in drug abuse. Shurtleff says studies of brain responses in adolescents illustrate youths' unique developmental scenario.

“The limbic system controlling motivation and drive is mature, while the prefrontal cortex, the part of the brain controlling executive function, is immature in adolescents,” Shurtleff says. What happens, he explains, is a sort of push-pull conflict that results in “younger people acting more impulsively.”

Shurtleff adds that exposure to an addictive substance at an early age greatly increases one's chances of addiction, and in the presence of a particular genetic profile those chances could be magnified.

Finding the differences

Genome-wide association studies, supported by NIDA, explore the effect of genetics on behavior by comparing genotypes of addicted vs. non-addicted people. This research involves taking blood samples from the two groups, extracting DNA and exposing it to genotyping, and looking at genetic variation in the two populations.

For example, subtle differences within a gene, such as one amino acid that changes how a protein is translated, can change how quickly a drug such as nicotine is metabolized. These genetic differences, or variants, also could affect executive and reward pathways that might account for some of the individual variability seen in addiction. Genetic differences might translate to individual variability at the receptor level, Shurtleff says, which could explain why some people are “resistors” to substances such as nicotine and others become addicted.

“Nicotine binds to nicotinic receptors in the brain to produce a variety of behavioral effects,” he explains. The medication Chantix for nicotine dependence, Shurtleff says, “targets the most common nicotinic receptor and effectively prevents nicotine from activating the receptor.”

Yet while the drug reportedly has a 25% success rate in smoking cessation, what will help the other 75% of individuals struggling to quit? Shurtleff says additional genetic studies are looking at new combinations of these nicotinic subunits to see how they might contribute to nicotine reward.

“Genetics is continually uncovering new biological targets and this is expanding our understanding of the biology of addiction,” he says. As new nicotinic targets are discovered, drug research could develop medications that act on those specific targets to help people struggling to quit smoking.

Compelling finding

A study entitled “Pharmacogenetic Approach at the Serotonin Transporter Gene as a Method of Reducing the Severity of Alcohol Drinking” (Johnson et al.), published in the March 2011 American Journal of Psychiatry, found compelling evidence of the genetic effect in people taking ondansetron, a medication that
has shown some promise in research regarding the treatment of severe alcohol dependence.

The investigation randomized a cohort of 283 people with alcohol addiction by their specific genotype of the serotonin transporter gene: the 5′-regulatory region of the 5-HTT gene (LL/LS/SS) and a polymorphism in the 3′-untranslated region. Study subjects were given either ondansetron or placebo for 11 weeks, along with cognitive-behavioral therapy. The authors reported conclusive outcomes in demonstrating the effect of genotype differences: “Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27 percent) than those who received placebo.”

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