What’s the next step in your research?

Nestler: One of the things we’re interested in is a better understanding of how drugs alter these transcription factors and what other things happen as a result. This remains somewhat of a mystery. That would be getting at a still more basic molecular level: How excessive dopamine stimulation leads to changes in transcription factor expression and what other genes are consequently altered. Many genes will turn out to be regulated, and we’d like to identify all these various genes.

What do you see as the most important changes in addiction research over the last five years? How has the field evolved?

Nestler: One change is the realization that the standard operant model of addiction, which is self-administration—an animal presses a lever to administer a drug—may provide a measure of the rewarding activity of the drug, but it doesn’t really model addiction. That realization has driven the field to develop much more sophisticated models that target addiction and craving—the core features of addiction in people. Another realization is that the acute target of the drug, the initial target, is just the beginning of how the drug causes addiction. Basically when a person first takes a drug and it gets into the blood stream and then the brain, that drug is going to bind to a particular protein. While that’s important to know, it can’t by itself explain addiction. Addiction is what happens afterward, and it involves many different proteins. It’s a slowly evolving process, like changes in gene expression. And I think a third area is the sense that the whole notion of reinforcement and reward, while very important, is just one component of addiction. This may be related to my first comment. In humans, and even in animal models, major components of addiction are learned. They involve conditioning or other types of learning. To really understand addiction, we need to understand learning, particularly that aspect of learning involved in what’s now called emotional memory.

What do you consider the most important research in the field right now?

Nestler: There are two areas, in some ways representing the opposite ends of the process. In my research, we try to understand the molecular basis of the near-permanent changes that occur in the addicted brain. This is a critical question for neuroscience in general—I see this as one of the major needs and one of our areas of focus. I think there is great progress being made here, and it’s actually a very exciting time for researchers. But as to how addiction is actually caused by these changes that drugs produce in these nerve cells—that's still completely unknown. Why is it that when you alter the functioning of the nucleus accumbens it leads to craving and contributes to emotional memories? That remains very obscure.

There’s some beautiful work being done in rodent models—and even more so in primate models—that makes it possible to look at more sophisticated behavior, to examine what it means for animal behavior when a particular nerve cell fires or doesn’t fire. This is part of the process of putting together how these nerve cells operate within more complex circuits, and then seeing how the circuits actually account for behavior. I am awed by the people who are trying to make progress in this area, who are learning how molecular and cellular changes lead to changes in the complex behavior that we know of as addiction. As a molecular biologist, it’s easy for me to conceive of molecular changes altering the functions of individual nerve cells. I can demonstrate that these molecular processes are important to the behavior we’re interested in. What I can’t do is go from there to how you get actual changes in behavior. That’s what these researchers are doing, and it’s very exciting work.