Learning, memory may reverse brain changes caused by addiction, UT Southwestern researcher says

Contact: Ann Harrell
or e-mail: ann.harrell@utsouthwestern.edu">ann.harrell@utsouthwestern.edu

DALLAS – Jan. 2, 2003 – An interaction between drug use and the expectation of drug reward can cause changes in the addicted brain that modify behavior as well as reduce cravings, a team of molecular psychiatry researchers that includes UT Southwestern Medical Center at Dallas scientists has demonstrated in a study appearing in this week’s issue of Nature.

Dr. David Self, associate professor of psychiatry at UT Southwestern and the study’s senior author, said the discovery shows that neurobiological changes in the brains of addicts, and the propensity for cocaine relapse, may be reduced by non-pharmaceutical means involving extinction training, learning and memory. Without this procedure, cocaine addiction causes persistent neurobiological changes that facilitate relapse despite attempts to abstain from further drug use.

“The paper describes an entirely novel and provocative phenomenon whereby extinction training during cocaine withdrawal produces changes in the brain receptors for the neurotransmitter glutamate (part of the brain’s signaling system) in an important brain reward region,” said Self, holder of the Lydia Bryant Test Professorship in Psychiatric Research.

Self and colleagues expressed the hope that information gained in this animal study will prove applicable to problems of human addiction. The study – with commentary in this week’s issue of Nature Medicine – was conducted at UT Southwestern and Yale University School of Medicine using transgenic technology to manipulate glutamate receptors developed by a Harvard Medical School researcher.

Cocaine usage reduces glutamate receptors in an area of the brain critical for communications – the shell, or outside, of the nucleus accumbens, which are part of the basal ganglia. The structure may become activated during reward-and-punishment activities. Glutamate receptor reduction contributes to persistent craving, Self said.

The extinction training used in the study is a technique in which rats were initially taught to press a bar to receive cocaine. Later, the rewards were removed, so the rats’ expectations were not met when they pushed the levers, thus extinguishing reinforcement for their learned behavior.

Half of the rats used in the study were given the extinction training. Rats undergoing drug withdrawal without the benefit of this cognitive training procedure actually lost some of their glutamate receptors. The researchers found that the amount of glutamate receptors in the nucleus accumbens’ shell area was related to the level of extinction during the training procedure.

“This finding is important because it demonstrates a profound interaction between drug use and experience in ultimately determining brain changes in the drug addiction process,” Self said. “They suggest that extinction-induced increases in glutamate receptors lessen the urge to seek cocaine in early withdrawal and promote resistance to relapse induced by stressful situations in prolonged abstinence.”

The researchers say that “our results also indicate that such upregulation (of receptors) may benefit cocaine addicts both directly, by facilitating control over the urge for cocaine, and, indirectly, by attenuating stress-induced cravings in prolonged abstinence.”

Self and the other researchers hope that extinction training may prove a way to restore balance to the brain area and aid in boosting willpower in those attempting to abstain from drugs. “It’s like taking the brain to the gym,” Self said. “The more this brain pathway is exercised with extinction training, the stronger the glutamate input becomes, and the brain is better equipped to deal with cravings and urges.”

In addition, they say that the study results suggest that behavior-based approaches, rather than pharmaceutical-based, have the potential to reverse or lesson the harmful neurobiological and behavioral consequences of chronic drug use, and this approach could prove useful in other mental illnesses. Self said extinction training in combination with certain pharmaceutical approaches could be even more beneficial.

UT Southwestern study authors include Dr. Kwango-Ho Choi, post-doctoral researcher of psychiatry; Kim Whistler, psychiatry research assistant; Diana Simmons, research assistant in the cell and molecular biology graduate program; and Dr. Lisa Monteggla, assistant professor of psychiatry.

Other authors, all from Yale, are Drs. Michael A. Sutton and Eric F. Schmidt, Christina A. Schad and David A. Karanlan. Dr. Rachael Neve of Harvard engineered the study virus.


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