NIDA Notes: What is your division’s agenda?
Joni Rutter: There’s a long-standing observation that not everyone who tries drugs becomes addicted. Some people are more vulnerable to addiction and some are more resilient. Our goal is to try to understand the individual differences that contribute to whether or not someone who takes a drug will become addicted to it.
Many factors contribute to those differences, and we break them down into three sets. One set is environmental—how a person’s experiences and exposures to drugs or other influences affect his or her risk for addiction. A simple example would be that if your friends smoke, you might be more likely to become a regular smoker and incur the risk for nicotine addiction that comes with regular smoking.
A second set of factors is developmental. The impact of an experience or an exposure often depends on when in a person’s life it occurs. Because the brain is very pliant from early life through adolescence, exposures during this period can make a profound difference in how vulnerable or resilient we are to addiction in the long run.
And finally, we are working to understand the genetics, epigenetics, and other biological processes that underlie drug use and addiction. Addictive drugs can hijack our brain circuitry and cause a rewiring that motivates a person to take more of the drug or make him crave it. So this area of research focuses on how the brain is constituted and how it works, how its neurons and other cells such as glia communicate with each other in these circuits, and then how drugs infiltrate and divert these circuits.
NN: Do genes play a large role in addiction?
JR: Genetic factors account for about 40 to 60 percent of a person’s vulnerability to drug addiction. Genetic studies have begun to identify gene variants that influence a person’s risk for drug use and addictive behaviors. We’ve made the most progress in relating gene variants to smoking behaviors.
We’re working toward a day when a physician might be able to review a patient’s genetic information and predict how she will respond to a particular treatment, for example an antismoking medication. Is it likely to help her, or will she experience side effects and maybe do better with an alternative treatment? There’s still a lot of work to be done in this area, but the evidence is building up and leading toward that goal.
Genetic studies are also giving us leads to the molecular and biological processes that underlie addiction. When we see which genes are involved, then we know which proteins are involved, and we can look at what those proteins do.
Using gene therapy to actually treat drug addiction is a long way off, however, and probably not a main goal. Studies have shown that addiction is a complex disease, with a large number of genes each contributing a little bit. It’s not like, for example, Huntington’s disease, where a single gene is responsible, and the problem is to find an answer to what that one gene does. And even that is a huge challenge.
NN: What are the most promising pathways to new addiction treatments?
JR: Nongenetic factors offer the most hope. They account for 40 to 60 percent of a person’s likelihood of becoming addicted, and they’re much more malleable than genetic factors.
Our overall strategy is to understand how addictive drugs act in the brain to produce and maintain addiction. We can then look for medications, behavioral therapies, or other interventions that will reverse or overcome those effects. This is how our current medications for smoking cessation and treating heroin dependence were developed. We’re now making a major push to identify molecules and processes involved in cocaine addiction and validate them as potential targets for pharmacological interventions.
A relatively new and very promising line of research looks at drugs’ effects on the activity levels of genes. These effects, called “epigenetic” effects, alter brain structure and function in ways that affect cognition and can give rise to addictive behavior. For example, they contribute to neuronal priming, whereby an initial drug exposure primes the brain’s reward system to react more intensely to subsequent exposures. They also underlie the long-lasting changes that distinguish addicted brains from nonaddicted brains.
Epigenetic studies, by pinpointing which genes drugs activate or silence, can shed light on the specific proteins and processes involved in addiction. And, if we can then prevent or reverse those effects, we may have powerful tools for preventing and treating addiction.
Unlike gene therapy, epigenetic treatment approaches would not involve actual manipulation of the DNA in genes. Instead, they would utilize epigenetic mechanisms that control how accessible genetic DNA is to transcription and translation into proteins. There are a number of epigenetic mechanisms at work in the body at all times. Just as drugs engage them to cause addiction, research may show us how to engage them to combat addiction.
NN: What makes your work exciting?
JR: One reason this is an exciting time to be studying addiction is that researchers are uncovering new knowledge at a truly unprecedented pace. That’s happening in large part because we have many new, truly cutting-edge tools and technologies at our disposal. Optogenetics is a great example. With this technology, scientists are using light to stimulate or shut down specific neurons in the brains of experimental animals. They then can observe the effects of that change on animals’ behavior, or they can track neurocircuitry by observing the fallout in other parts of the brain. We also have the ability to create very fine-tuned molecular tools—for example, molecules that we can use to modulate those epigenetic processes and observe the effects.
We’re also benefiting from the huge advances in data storage and computing power that have taken place. That’s given rise to what we call “Big Science.” The promise of Big Science is that we will be able to integrate all of our behavioral, molecular, genetic, epigenetic, and other findings into a multidimensional, reasonably complete picture of addiction—what it is, and how to prevent and cure it.