June 4, 2004

VUMC hosts conference on addiction; Nobel laureate Greengard keynote speaker

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Nobel laureate Paul Greengard, Ph.D., was the keynote speaker at the “Frontiers in Addiction Biology: Genomics and Beyond” conference.

VUMC hosts conference on addiction; Nobel laureate Greengard keynote speaker

Drinking…smoking…eating…sex…gambling. Every human activity seems to have the potential to result in addiction.

Once seen as simply a bad habit and moral weakness, addictions are now recognized as genuine medical conditions, with genetic and physiological components. In fact, drug and alcohol addictions are one of the most highly heritable psychiatric disorders.

The search for the biological foundations of addiction was the topic of the Vanderbilt University Summer Conference held May 23-26. More than 100 scientists from around the world attended the conference “Frontiers in Addiction Biology: Genomics and Beyond.”

Nobel laureate Paul Greengard, Ph.D., of Rockefeller University was the keynote speaker (see sidebar on page 6). In 2000, he was awarded the Nobel Prize in Physiology or Medicine for his research on the molecular pathways nerve cells use to communicate and how the neurotransmitter dopamine is involved in this communication.

The conference brought together many of the world’s leading addiction researchers to discuss recent advances in the genetics and neurobiology of addiction. Topics included the genetic basis of alcoholism and psychostimulant abuse, animal models of addiction, and the application of brain imaging technologies in addiction research.

In the first session, researchers discussed their attempts to find genes associated with alcohol use and dependence, turning up some interesting contenders.

David Goldman, M.D., chief of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism, has identified a candidate gene in a population of Native Americans. The gene codes for the enzyme COMT (Catechol-o-methyltransferase). Different versions of the gene, or variants, seem to be linked to different “types” of alcoholism.

“In a population of alcoholics whose major vulnerability is anxiety, they tend to have the COMT gene that is more anxiety-associated. Other populations of addicts in whom the vulnerability is behavioral control are more likely to have the other form of the gene,” Goldman said.

Finding genes linked to particular behavioral traits has implications, not only for drug addiction, but for a variety of other psychiatric disorders.

“We were interested in the genetic vulnerability factors in psychiatric disorders, which will ultimately enable us to improve diagnosis and individualize treatment,” Goldman said.

While some scientists pursue the biological basis of addictions at the genetic level, others investigate what is different about the addict’s brain at the level of neuroanatomy and behavior.

Hans Breiter. M.D., of Massachusetts General Hospital and Harvard University Medical School, is trying to bridge the research gap between these approaches. Breiter uses brain imaging techniques to find abnormalities associated with addiction, in hopes of linking such changes to genes.

Breiter and others have found that cocaine addicts have structural and functional differences in brain areas that process reward and aversion, or “pleasantness” and “unpleasantness,” respectively. One brain region, the amygdala, showed a 23 percent reduction in cocaine addicts very early in their addiction. This suggests that the change is not a result of cocaine abuse, but may be a predisposing factor to cocaine addiction.

He is currently looking for similar changes in the brains of non-addicted family members. This, he says, will set the stage for finding genes that may predispose a person to drug addiction.

Although brain imaging technology has been used clinically for some time, only recently has it been adapted for use in rats and mice — popular research subjects in addiction biology.

A pioneer in the field of magnetic resonance imaging (MRI), John Gore, Ph.D., director of the Vanderbilt Institute of Imaging Science, addressed the use of imaging technologies in small animals. Gore and his team created Vanderbilt’s Center for Small Animal Imaging core, which includes MRI, micro-CT and micro-PET technologies scaled down for use in small animals.

These technologies offer many advantages, Gore said. They save money and animal resources, they are non-invasive but highly sensitive, and allow a researcher to get detailed information about brain anatomy, physiology and biochemistry.

This technology also has much to contribute to addiction research. Brain imaging can show the effects of drugs on neurotransmitter systems and receptors in the brain, and those changes can be correlated with behavior.

“In the next few years, we will see what this technology really can contribute to the field of addiction,” Gore said, predicting a bright future for MRI and micro-PET in addiction research.

A protein at the center of it all

by Melissa Marino

Understanding how the 100 billion nerve cells of the human brain communicate might seem like a daunting task. But the research of Nobel laureate Paul Greengard, Ph.D., has identified common pathways used by many of the brain’s neurotransmitters, making sense out of apparent chaos.

In his keynote address, Greengard described his work detailing a process called slow synaptic transmission. This is the process that most neurotransmitters, including dopamine, use to communicate.

When dopamine is released from a nerve cell, it first acts on receptors on other nerve cells, triggering a complex cascade of reactions that alter certain key proteins inside the cell. This cascade eventually leads to a protein called DARPP-32.

Dopamine is not the only neurotransmitter that affects DARPP-32. Nearly all of the neurotransmitters that Greengard has examined seem to converge on this protein.

“In the beginning, there was DARPP-32,” Greengard said, highlighting the central importance of this protein.

“This molecule provides an integration mechanism. Nerve cells get information from, on average, 1,000 other nerve cells. What the cell needs to do is to evaluate all the information coming into it. The only way it can is to have molecules that “tabulate” what is going on, like a master calculator,” Greengard explains.

“DARPP-32 is a key component of that integration mechanism. All of these neurotransmitters are, through direct or indirect pathways, regulating the phosphorylation of DARPP-32. This controls whether the cell is going to fire an impulse or not.”

According to Greengard, virtually all drugs of abuse act on the dopamine system in the brain and can perturb DARPP-32 function. Greengard has found that the effects of many types of drugs (caffeine, marijuana, amphetamine, LSD, etc.) were completely abolished in mice that lack DARPP-32.

Greengard plans to look for variants of the gene encoding DARPP-32 in humans. If found, this might suggest a common link underlying susceptibility to a number of addictions.