Dr. Eric Nestler

Eric J. Nestler, MD, PhD, will discuss the biology of depression this Saturday at Mount Sinai Medical Center in New York as part of NARSAD’s Healthy Minds Across America series. Details and free registration are online here.

Welcome, Dr. Nestler. You have done a broad range of research into both addiction and depression.  Can you share with us first some of your recent findings concerning addiction?

We have been focusing on the mechanisms by which repeated exposure to drug abuse changes the brain to cause addiction. Given that the behavioral abnormalities that cause addiction are long-lasting—some people remain at risk for relapse despite years of abstinence—we have focused on drug-induced changes in gene expression as the basis of addiction.

Our work is carried out in laboratory animals, such as rats and mice, which choose to self-administer and addict themselves to the same range of drugs as people self-administer and addict themselves to. This self-administration behavior in animals, like in humans, is determined roughly half by the individual’s genes and roughly half by the environment. For example, we know that chronic exposure of rats and mice to stress increases their vulnerability for addiction.

The availability of these animal models has made it possible for the field to identify areas of the brain—referred to as brain reward regions—which mediate the addicting actions of drugs abuse. Our research utilizes advanced gene discovery methods to identify those genes within these brain reward regions whose expression levels are altered after chronic administration of a drug. We have identified several such genes and have utilized genetic mutant mice and viral-mediated gene transfer to demonstrate that drug regulation of these genes does in fact mediate aspects of drug addiction, namely, specific behavioral abnormalities that summate to cause addiction.

Has your research led to pharmaceutical interventions or other discoveries for the treatment of addiction?

As we identify genes involved in the addiction process, it is possible to embark on drug discovery programs to synthesize novel small molecules that interfere with the abnormal patterns of gene expression. This work is underway. It will still take 5-10 years, at a minimum, to transform these discoveries into new treatments for humans, but the work has pointed to several fundamentally new pathways forward.

Have you made any discoveries about how to reduce cravings and urges?

Yes. Several of the drug-induced changes in gene expression that we have found in the brain’s reward regions mediate craving and urges, to the extent these behaviors can be studied in rats and mice.

Do you have any comments about Suboxone? Despite the controversy, we have heard from others, including Dr. Bryan Wood, that Suboxone is quite effective.

Suboxone is promising new treatment for opiate addiction.

Are there any similarities (or relationships) between the molecular basis of addiction and of depression?

Many people with depression suffer a deficit in “reward”, the ability to feel pleasure and satisfaction. For this reason, we and others have proposed an important role for brain reward regions in mediating some of the symptoms of depression. Our research in animals has provided strong support for this hypothesis and, indeed, some of the same genes are regulated within these reward regions in response to chronic stress as seen in addiction models.

Human brain imaging studies have also lent support for the role of brain reward regions in depression. This is interesting, because many addicts also have reward deficits, at least for natural rewards (food, sex, social interactions). This work has revealed genes that could be modified to enhance the experience of reward and thereby repair the reward deficit shared by some people with depression and addiction.

Thank you so much for your time, Dr. Nestler.

Eric J. Nestler, MD, PhD, is the Nash Family Professor of Neuroscience at the Mount Sinai School of Medicine in New York, where he serves as Chair of the Department of Neuroscience and Director of the Mount Sinai Brain Institute. The goal of Dr. Nestler’s research is to better understand the molecular mechanisms of addiction and depression based on work in animal models, and to use this information to develop improved treatments of these disorders.

You can learn more about Dr. Nestler’s research into addiction and depression at his web site.

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    Last reviewed: 27 Apr 2010