Few researchers in this field have had the impact of Eric J. Nestler, a psychiatrist and pharmacologist at The University of Texas Southwestern Medical Center at Dallas. In the past two decades, Nestler has seen nearly 20 of his published papers collect more than 100 citations each. Two papers have racked up over 300 citations, including his 1992 Journal of Neuroscience article on "Molecular mechanisms of drug addiction," which has tallied nearly 400 to date. Nestler, in fact, got an early start in high-impact research: nine of his first ten publications, all written with his Ph.D. advisor Peter Greengard, appeared in either the Proceedings of the National Academy of Sciences of the USA, Science, or Nature, culminating with a 1983 Nature article, "Protein phosphorylation in the brain," which has been cited more than 300 times.

Nestler, 47, obtained his undergraduate degree in 1976 at Yale University, where he also earned his doctorate in pharmacology in 1982 and his medical degree the following year. In 1987, Nestler joined the faculty at Yale in the departments of psychiatry and pharmacology before eventually becoming director of the Yale Center for Genes and Behavior in 1997. This past year he moved to The University of Texas Southwestern Medical Center where he is chair of the psychiatry department and chief of the psychiatry service at Parkland Memorial Hospital.

What started you off studying addiction?

Nestler: When it became time to set up my own laboratory, after getting my Ph.D. with Paul Greengard on signal transduction mechanisms in the brain and then doing a residency in psychiatry, I wanted to study phenomena of some relevance to clinical psychiatry. I thought addiction would be a good focus because the animal models available for addiction were pretty well established. I knew which brain regions to look at, and I knew that once molecular changes were identified, the behavioral models would make it possible to study their significance.

What brain region did you start in?

Nestler: A region called the locus coeruleus. It was known that the locus coeruleus was involved in some way in mediating physical opiate addiction. For instance, if you treat animals with opiates repeatedly and then inject the locus coeruleus with an opiate antagonist such as naloxone, you can precipitate withdrawal or cold turkey. Or if you take a normal animal and stimulate the locus coeruleus electrically, you can reproduce some of the symptoms of opiate withdrawal. So the locus coeruleus is probably one of many regions that mediate opiate withdrawal. Back in the mid-1980s, a senior investigator in my unit, George Aghajanian, showed that neurons of the locus coeruleus that make norepinephrine showed electrical responses equivalent to tolerance, dependence, and withdrawal. This was a great cellular model of opiate addiction, and it had some behavioral relevance. In collaboration with George, we were able to show that chronic opiate use up-regulates the cyclic AMP pathway. It is a big part of why those neurons function differently after chronic opiate use. We were excited about that—being able to identify a molecular change that opiates cause in a certain type of neuron, relating that molecular change to altered functioning of individual nerve cells, and then being able to show behavioral consequences of those changes.

In the early 1990s you shifted gears and also brain regions. Can you tell us about that research?

Nestler: We wanted to see whether similar molecular changes were occurring in brain regions more closely related to the psychologically addicting aspects of drug abuse. Locus coeruleus neurons are involved in withdrawal, but not in the intense craving and seeking of drugs that are characteristic of addiction. That was inferred from lab animals. If you give animals a choice to self-administer drugs and then lesion the locus coeruleus, you won’t stop them from learning how to do it, or stop them from doing it.

Which brain regions are involved in the craving seen in addiction?

Nestler: The dopamine neurons in the ventral tegmental area and their projections to the anterior limbic system. The particular brain region that researchers focused on is called the nucleus accumbens. Research had shown that if you lesion the ventral tegmental area or the nucleus accumbens, you do block drug self-administration behavior. We were able to show that the same type of up-regulation of the cyclic AMP pathway also occurs in the nucleus accumbens. We’ve since gone on to relate those changes in the cyclic AMP pathway to the behavioral features of addiction—to reinforcement, reward, and addiction.

Isn’t the nucleus accumbens considered the reward center of the brain?

Nestler: It is. That was based on a large literature from many laboratories. We were taking advantage of that literature and found that when we fiddle with the cyclic AMP pathway, we alter those reward mechanisms. And we found that several drugs of abuse up-regulate the pathway. This provided evidence that up-regulation of this pathway may be a general response to drugs of abuse.

What are the changes in the brain and in brain cells that mediate this up-regulation of the cyclic AMP pathway? In other words, what does chronic drug use do to these brain cells?

Nestler: To answer that, we looked at transcription factors. We found evidence that two in particular seem to be involved: one is called CREB and the other is called DeltaFosB, which is one of a family of transcription factors that are known to be induced by many stimuli in the brain. These factors generally appear very quickly but also go away quickly, within a few hours. Once DeltaFosB comes on, however, it stays on. It’s unique. In response to chronic drug use, each exposure to the drug leads to a little bit more of the factor being made. Because it’s so stable, it accumulates and becomes a dominant transcription factor in the brain. When you take the drug away, it still persists for several weeks or a few months. As far as we know, that’s the longest-lasting molecular change anyone has identified in drug exposure, although it’s still not permanent. We've recently been working with transgenic mice that over-express either DeltaFosB itself in the nucleus accumbens or an inhibitor of DeltaFosB in the nucleus accumbens. When mice over-express DeltaFosB selectively in the nucleus accumbens only in adult animals, the animals show greater sensitivity to cocaine and morphine. They also show greater interest in cocaine. When we over-express the inhibitor, the animals show less interest. We’re excited, of course, about these results.
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