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Stanford Report, October 9, 2002

Symposium explores the science of addiction treatment

By AMY ADAMS

Although the fried egg imagery of the 1980s anti-drug advertising campaign was less than exact, the ads did get one thing right: a brain on drugs is permanently changed by the experience. That’s according to research presented at an addiction symposium at Fairchild Auditorium Friday.

The symposium, organized by Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in psychiatry and behavioral sciences, and sponsored by the Stanford Brain Research Institute, assembled addiction experts from across the country to discuss how drugs alter the brain’s chemistry and physiology.

"The experience of drug-taking leaves a permanent mark on the brain," Malenka said during his presentation. These changes make the brain more sensitive to drugs and cause a person to crave drugs. "Drugs lead to wanting, not liking," he added.

Scientists’ understanding of addiction comes, in part, from new imaging technologies that pinpoint regions of the brain that are active when a person takes or craves a drug. These images have guided researchers to an almond-shaped structure in the brain called the amygdala, which helps regulate a person’s emotions, and the nucleus accumbens, which is involved in the brain’s reward and punishment feedback.

Hans Breiter, MD, director of the Motivation and Emotion Neuroscience Center at Harvard Medical School, said he sees different regions of the brain become active in addicts who receive a drug and addicts who are shown pictures of other people receiving the drug. People without an addiction or who receive a placebo don’t show any activation of those regions. "These people clearly had an adapted brain," Breiter said.

Some of the changes that take place in a drug-addicted brain include stronger connections between neurons in the nucleus accumbens — one of the regions highlighted by Breiter’s imaging work. Malenka has found that neurons in this region form much tighter connections after he injects mice with cocaine rather than a placebo solution. This change lasted for several days after the injection.

In addicted mice, the neuron regions that make connections with neighboring neurons — called dendritic spines — grow more densely branched and able to form connections with more neurons. This change seems to come about when a gene called delta FosB becomes active after many months of drug addiction, said Eric Nestler, MD, PhD, chair of the department of psychiatry at the University of Texas Southwestern Medical Center.

Nestler said several genes are turned on soon after rodents take a drug, but that delta FosB becomes active in animals that take the drug chronically. He created mice that produce the delta FosB protein in their brains even in the absence of a drug. The mice who made delta FosB learned how to get cocaine from an apparatus more quickly than their litter mates, were more sensitive to cocaine, and were willing to work harder to get the drug once they had become addicted.

Nestler added that delta FosB remains in the brain even after an animal has been off cocaine for many months, which could explain why an addict has such a hard time staying off the drug. "Once it is turned on, delta FosB maintains an addiction," Nestler said.

Nestler said this work could lead to treatments. "The goal is to understand what causes addiction and prevent it from occurring," said William Mobley, MD, PhD, the John E. Cahill Family Professor in the School of Medicine, who hosted the morning session.

One step toward a molecular treatment for addiction came from Charles O’Brien, MD, PhD, vice chair of the department of psychiatry at the University of Pennsylvania, who discussed his studies using the drug naltrexone to treat alcoholism. Naltrexone blocks receptors in the brain that bind opioids and lead to the pleasurable sensation from alcohol or heroin. It has been used since the 1980s to treat heroin addiction.

In a clinical trial, recovering alcoholics who took naltrexone lost the craving for alcohol and were less likely to relapse than people taking a placebo. People on naltrexone reported less feeling of euphoria when they drank than alcoholics who weren’t on the drug. The downside is that people were likely to relapse when their naltrexone treatment ended. "Naltrexone doesn’t work if you don’t take it," O’Brien said.

"This research is an example of how modern research will make inroads into addiction and other serious brain disorders," Malenka said.




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