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Stanford Report, February 26, 2003

Link found in brain response to addictive drugs, stress


Drug addicts may prefer some drugs over others, but their brains all have something in common. Whether it’s uppers or downers, addictive drugs tweak the same addiction-related neurons, causing them to become more sensitive, say researchers at the medical center.

"What we have identified is a single change caused by drugs of abuse with different molecular mechanisms," said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in psychiatry and behavioral sciences at the School of Medicine. Malenka is the senior author of a paper in the Feb. 20 issue of the journal Neuron which describes the molecular changes that occur as a result of taking addictive drugs.

When people take addictive drugs, neurons in a region of the brain called the ventral tegmental area (VTA) transiently ramp up production of dopamine, a chemical that acts as a neurotransmitter. The new research shows that the drugs also increase the sensitivity of neurons in the VTA. Researchers suspect it’s the release of dopamine in addition to this enhanced sensitivity that leads to addiction.

In a paper published last year, Malenka and researchers at UC-San Francisco showed the molecular changes that underlie this increased sensitivity in mice that were given cocaine. In the VTA, a brain chemical called glutamate normally activates neurons to release dopamine. In the cocaine study, the researchers found that after the mice had been given cocaine, their neurons became more responsive to glutamate for as long as a week afterward.

Now the researchers have shown that cocaine, morphine, amphetamines, nicotine and alcohol all cause the dopamine-producing neurons to become more sensitive to glutamate. Interestingly, the researchers also found that stress triggered an identical set of changes in the brain. Drugs that affect the brain but aren’t addictive don’t cause dopamine-producing neurons to become more sensitive.

Malenka pointed out that while stress itself may not be addictive, it can trigger a reformed addict to slip. "When drug addicts who are in remission and are doing fine are subject to stress, they very often relapse," he said. The current work could help researchers understand the link between stress and addiction.

Although addictive drugs and stress triggered the same changes in the VTA, further studies have shown that they do so through different means. When the researchers gave mice drugs that block the molecular effects of stress, the stressful situation no longer made the dopamine-releasing neurons more sensitive to glutamate. This same drug did not block the effects of cocaine.

It turns out that the molecular changes Malenka and his colleagues discovered have long been known to be involved in learning and memory. In both processes, neurons become more sensitive to glutamate.

Malenka said this work is an early step toward understanding how addictive drugs affect the brain. "It’s just the beginning of the story, but given that it is

happening in the VTA it is likely to lead someplace," he said. In the long term, this work might lead to drugs that block the addictive response, he added. The question will be how to block the addictive effects of drugs without impairing the normal role of dopamine-producing neurons in learning and memory.

Other researchers who contributed to this study include postdoctoral fellows Daniel Saal, PhD, and Yan Dong, PhD.

Symposium explores the science of addiction treatment (10/9/02)

Malenka named Nancy Friend Pritzker professor (7/24/99)