Taking Aim at Addiction

Researchers attack complex disorder from many angles, from basic biology to impact on society

Oct. 5, 2009

The work of a group of researchers at The University of Texas at Austin revolves around a central question:

“Why can drugs hijack the brain to such an extent that people ruin their lives, lose everything they have simply to get more of the drug?”

That’s the question posed by R. Adron Harris, an alcoholism researcher and the director of the Waggoner Center for Addiction and Alcohol Abuse.

“That’s part of the fascination,” Harris said of addiction research. “You can pull at that from all different levels.”

More than two dozen researchers at The University of Texas at Austin pull at the question of addiction from all levels. They study the basic biology of addiction. They study how to reduce drug and alcohol abuse. They study American culture through the lens of addiction.

The research is performed in the schools and colleges across campus, from Social Work and Pharmacy, to Natural Sciences and Liberal Arts, to Education and Communication.

The university has more than $7 million in research projects funded by the National Institute of Drug Addiction and the National Institute of Alcoholism and Alcohol Abuse. Other funding comes from other government agencies and foundations.

To illustrate the research in addiction and abuse, here are snapshots of several researchers working across the continuum.

Hitoshi Morikawa: Your brain, on drugs, learns too much
R. Dayne Mayfield: Finding the genes involved in alcohol abuse
Lori Holleran Steiker: Listening to kids to reduce drug abuse
Kim Fromme: What happens to college students when they drink
Mark Smith: Looking at America through drugs

Your brain, on drugs, learns too much

One of the most famous science experiments is the one involving Pavlov and his dog in which Ivan Pavlov conditioned the dog to salivate at the sound of a bell.

Hitoshi Morikawa
Hitoshi Morikawa want to find ways to interfere with the brain’s capability to “overlearn” drug-associated behavior.

Addictive drugs affect the brain in a similar but more powerful way, says Hitoshi Morikawa, a neurobiologist in the Waggoner Center for Alcohol and Addiction Research.

“We think addiction is a form of pathological overlearning in which the brain remembers too much the association between certain environmental stimuli and drug-seeking or drug-taking behaviors,” he said.

For example, ex-addicts who return to their hometowns might find themselves in places where they scored drugs in the past, looking for street dealers, he said.

“It’s like an automatic response to a previously learned stimulus,” said Morikawa, who was a medical doctor before he started his research career.

Such form of stimulus-response association, he said, has been hardwired into brain circuits by dopamine, a transmitter for learning in the brain.

“The synaptic connections that are active when dopamine levels are high will be strengthened more efficiently,” he said. “All addictive drugs are very efficient in elevating dopamine levels in various brain areas because they all directly get into the brain and stimulate the dopaminergic system by their pharmacological actions.”

Morikawa’s laboratory injects drugs into slices of the brains of rats and mice to search for where these interactions are taking place. Electrophysiological recordings and fluorescent imaging are used to see the neuronal activity generated by the drugs.

“We have found, for example, in animals that have been repeatedly exposed to drugs like amphetamine or ethanol that plasticity is dramatically enhanced,” he says. “Which might account for the overlearning of the cues, the environmental stimuli associated with addictive drugs.”

That discovery, in turn, could indicate that there might be a treatment for addiction that would interfere with the learning of drug-associated behaviors.

“Our goal is to provide a powerful pharmacological intervention for addiction,” Morikawa said. “When combined with other treatment modalities such as psychotherapy, this might help addicts unlearn the environments and behaviors related to drugs.”

Finding the genes involved in alcohol abuse

Research scientist R. Dayne Mayfield analyzes the tissue of post-mortem human brains to identify genetic targets in the brain where alcohol acts.

R. Dayne Mayfield
Dayne Mayfield looks for patterns of relationships between gene networks that can lead to alcoholism.

“The animal models are great but the biological systems can be very different,” he says. “By utilizing human brain tissue we go straight for the potential targets in humans.”

Mayfield, a researcher in the Waggoner Center for Alcohol and Addiction Research, says that the long-term goal is to identify targets that might be important for medication development for alcoholism.

The tissue, obtained from sanctioned brain banks, is well-traveled by the time Mayfield sits down to analyze the data elicited from it.

First, he receives a shipment of brain tissue, sent by overnight delivery from a brain bank in Sydney, Australia.

Then Mayfield and his colleagues extract RNA from the tissue and ship it to the National Institutes of Health Microarray Consortium at Yale University in New Haven, Conn. There it goes through a microarray analysis, which identifies altered patterns of gene expression in these brain regions.

When the results return to Austin, there are about 50,000 pieces of data per sample to be reckoned with.

Those data are narrowed down through several steps involving sophisticated statistical methods.

“Then we’re down to a couple of hundred important genes,” Mayfield says, “and we try to find the patterns that are in those few hundred.”

Visualization of the data shows patterns where genes and families of genes have been active.
So far, findings indicate that same families of genes keep showing up including some involved in nerve degeneration, the regulation of myelin (an insulator of nerve cells) and cell degeneration.

In addition to microarray analysis, Mayfield plans to use new equipment at the university, next-generation sequencing technology, to investigate, for the first time, gene changes in the human brain that result from alcohol abuse.

“The unprecedented depth and accuracy in transcript detection and identification will almost certainly improve our understanding of drug action,” he says.

Mayfield say there won’t be just one or even just a few genes involved in alcohol’s impact on the brain.

“Alcohol abuse is a very complicated disorder so there’re going to be probably many players that underlie the condition,” he says.

Listening to kids to reduce drug abuse

Lori Holleran Steiker, an associate professor and assistant dean of undergraduate studies in the School of Social Work, conducts research used in tailoring drug prevention programs for middle schools and high schools.

Lori Holleran Steiker
Lori Steiker Holleran is investigating the idea that becoming “preventionists” nudges students to confront their own drug use.

Listening to what the young people have to say is crucial to her research and in drug prevention, she says.

Her work in prevention began when she was part of the team of researchers that developed a drug prevention program called keepin’ it REAL, an acronym for Refuse, Explain, Avoid and Leave. The program is used in grades six through eight around the country.

Holleran Steiker’s research engages youth in order to adapt some of the program’s materials for their local community or school culture. Their involvement includes making videos and adding relevant alcohol- and drug-related scenarios to the program.

“‘For students, by students’ was the mantra,” says Holleran Steiker, who had been an addictions therapist before she started her research career.

In recent work with the program, she found that there was an interesting effect on the high school-aged youths who develop the materials. It made them stop and think.

Some of the young people told Holleran Steiker that they didn’t realize how much they were using drugs until they stepped into their new role of “preventionist” or that they had become aware how using drugs around younger siblings might affect them.

“My hypothesis is that they actually may shift their stage of change, level of readiness or awareness for change based on that experience,” she says.

That finding is from her research’s qualitative component, she says, but she intends to study it more empirically.

Holleran Steiker says she heard someone say adolescents aren’t used to being considered experts in anything, but she believes in the value of their expertise in their own experiences and in ways to help other kids make informed decisions about drugs and alcohol.

“I say to them, ‘You’re the experts. You tell me.’ I think that stance is critical in this work.”

What happens to college students when they drink

Kim Fromme, a psychology professor, studies drinking among college students.

Kim Fromme
Kim Fromme’s multi-year study, the UT Experience!, is producing much information about why and when college students drink and what happens after they do.

She studies why they drink, when they drink, how much they drink and what they do after they drink. And, in the Bar Lab, an actual bar set up in the Seay Building, she studies them while they drink.

She takes what she learns from this research to design more effective programs to help college students deal with drinking and drugs.

Fromme says information culled from her research can help college kids reduce the risks they take.

Among the projects her lab is working on is one called the “UT Experience!” It follows students and their experiences from freshman year to past graduation. They fill out questionnaires–some of them very detailed–online.

The project is producing a wealth of information about college students and drinking.

An example is information the project uncovered about light drinkers that might help them avoid risky behavior they normally wouldn’t engage in, but might if they drink too much.

The research found that when light drinkers go off the deep end–say, consuming a dozen or so beers during the OU weekend festivities in Dallas–they become far more likely to engage in risky behavior. They deviate from their typical drinking norm.

That’s when they are more likely to be sexually assaulted, commit sexual assault or engage in property crimes or vandalism.

Preventive drinking programs are usually one-size-fits all and offer little information relevant to light drinkers.

“Now here’s something for them,” Fromme says. “We can say it’s great that you drink less than the average college student, but when you deviate from your low drinking norm you are at greater risk for some of these behaviors. That’s an example of how we can take this kind of data and then fold it back into prevention.”

Looking at America through drugs

Mark Smith is an associate professor of American studies and drugs are the prism through which he studies America.

Mark Smith
Mark Smith says that while American attitudes toward drugs have changed over the course of American history, they’ve remained stable for the past several decades.

“My interests are in looking at the various ways Americans have perceived and reacted to various drugs over time, how the polices have changed toward them,” he said.

For example, there were times when alcohol was illegal and morphine and heroin were not.

“When upper class women were doing morphine in the latter part of the 19th century, it was not criminalized, it wasn’t even seen as a problem,” Smith says.

The first drug other than alcohol to be criminalized was smoking opium in San Francisco.

“The only people who smoked opium were the Chinese immigrants and the occasional gambler or gangster in the underworld,” Smith said.

The crackdown came when more gamblers started using opium and the drug started to spread to the general society.

“As long as the Chinese themselves were using it, it wasn’t quite a threat,” he said. “Once they went away from that, it became a huge threat.”

That pattern continued until after World War II.

Then, as the world became more complex, drugs took on a symbolic role, a symbol of all that’s gone wrong in society, Smith said.

“It (addiction) reflects our lack of power over our own lives, because addiction literally is the lack of power over our own lives,” he said.

That attitude picked up steam in the 1980s with the War on Drugs. That was also a time when the United States was licking its wounds over Vietnam and Watergate.

“While we have gone beyond most of the stereotypes and emotional reactions of the ’70s and ’80s, our society retains its dogmatic view about drugs and refuses to entertain differing views on any of the drugs,” Smith says. “With regard to drugs, our attitudes have changed amazingly little over the past 30 or 40 years.”

For more information, contact: Tim Green, Office of the Vice President for Research;
Banner and inside photos: Christina Murrey