All addictive drugs, including alcohol, cocaine, amphetamines, morphine, and nicotine, affect neurons in the same area of the brain, which suggests that it may be possible to someday contrive a universal approach to treating addiction, according to researchers at Stanford University. These drugs—stimulants and depressants alike—affect the same addiction-related neurons, causing them to become more sensitive.

“What we have identified is a single change, caused by drugs of abuse with different molecular mechanisms,” said Robert C. Malenka, MD, PhD, who is the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences at the Stanford University School of Medicine. Dr. Malenka, senior author of the study, detailed his team’s findings in the February 20 Neuron.

THE GLUTAMATE/DOPAMINE CONNECTION

Dr. Malenka and colleagues found that addictive drugs cause neurons in the ventral tegmental area of the brain to transiently increase production of dopamine. They also showed that the drugs increase the sensitivity of neurons in the ventral tegmental area. Therefore, the investigators hypothesized that it is the release of dopamine, in addition to this enhanced sensitivity, that leads to addiction.

In a report published last year, Dr. Malenka, along with researchers at the University of California, San Francisco, showed the molecular changes that underlie this increased sensitivity in mice that were given cocaine. He explained that in the ventral tegmental area, 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 up to a week later.

ADDICTION AND STRESS

Meanwhile, Dr. Malenka also found that stress triggers changes in the brain identical to those of cocaine. He pointed out that while stress itself may not be addictive, it can cause a reformed addict to relapse. “When drug addicts who are in remission and doing fine are subjected to stress, they very often relapse,” he said. He added that this finding could help researchers ultimately understand the link between stress and addiction.

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

Dr. Malenka noted that drugs that affect the brain but are not addictive do not cause dopamine-producing neurons to become more sensitive. In addition, he said, the molecular changes that his team discovered are involved in learning and memory. In both processes, neurons become more sensitive to glutamate, he noted.

Dr. Malenka believes that the current study 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 ventral tegmental area, it is likely to lead someplace,” he said. He hopes that this work will eventually aid in developing drugs that block the addictive response. The key, he said, will be blocking the addictive effects of drugs without impairing the normal role of dopamine-producing neurons in learning and memory.

Suggested Reading
Beurrier C, Malenka RC. Enhanced inhibition of synaptic transmission by dopamine in the nucleus accumbens during behavioral sensitization to cocaine. J Neurosci. 2002;22:5817-5822.
Saal D, Dong Y, Bonci A, Malenka RC. Drugs of abuse and stress trigger a common synaptic adaptation in dopamine neurons. Neuron. 2003;37:577-582.

Return to table of contents