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.