Source of withdrawal pangs found in brain.

It's a cruel punishment for drug dependency. Those who finally decide to kick the habit or who simply can't get hold of any drugs may experience withdrawal, complete with shaking and sweating. Many addicts have no doubt wondered what could be making them feel so bad.

According to Glenda C. Harris and Gary Aston-Jones of Hahnemann University in Philadelphia, it's dopamine, a chemical messenger, in the brain's nucleus accumbens that helps impose this harsh sentence. Researchers disagree, however, on the finding's clinical implications.

Their new results, reported in the Sept. 8 LANCET, further support dopamine's good guy-bad guy image: This chemical helps provide the high and then turns against users when they fail to deliver the goods -- more drugs (SN: 6/30/90, p.406).

Uncovering the role of the nucleus accumbens in withdrawal "is an important finding...[that] will stimulate a lot of new research," says Roy A. Wise of Concordia University in Montreal.

Other experiments had shown that dopamine concentrations in the accumbens can crash when addicted animals go off drugs. When animals get drugs that ward off the symptoms of withdrawal, dopamine concentrations in the accumbens don't decrease. But these findings demonstrated only an association between dopamine and withdrawal -- not a cause-and-effect relationship, contends Aston-Jones.

To demonstrate how dopamine contributes to the physical effects of going cold turkey, Harris and Aston-Jones gave a dopamine agonist, a compound that mimics dopamine's action, to rats addicted to morphine. The agonist "significantly attenuated all [physical] withdrawal symptoms measured," the investigators assert. The stronger the dose, the milder the symptoms.

Pretreating the rats with a dopaminereceptor antagonist, which blocks the receptors, prevented the agonist from working its magic, they report.

Piping an agonist into the accumbens that targets a specific dopamine receptor, the D2, proved particularly effective at preventing withdrawal symptoms. Giving a similar injection into parts of the brain near -- but not in -- the accumbens did nothing to stop them. And a different agonist that acts on the D1 receptor sometimes made the physical pangs of not getting the drug worse, Harris and Aston-Jones found.

Finally, blocking dopamine receptors in the accumbens seemed to turn on physical withdrawal symptoms in morphine-dependent animals but not in nonaddicted animals.

Because other researchers have injected opiate antagonists into the accumbens of opiate-addicted animals and produced only mild signs of withdrawal, Harris and Aston-Jones conclude that "the accumbens may not be a major site for the initiation of opiate withdrawal symptoms." Instead, it may help regulate the body's response to getting off opiates.

The findings have "strong clinical implications," argues Aston-Jones, since they show which dopamine receptors influence withdrawal symptoms. Now, he says, researchers need to test drugs known to activate these receptors.

While Wise doubts the new study will result in better treatments for addicts, "I'm sure other people will [say it will]." He explains: "I'm more conservative."

Indeed, Derek van der Kooy of the University of Toronto disagrees with many of the team's conclusions regarding dopamine. His studies suggest that dopamine agonists and antagonists both block the ill effects of leaving drugs behind. Withdrawal involves a change in the firing pattern of the neurons activated by dopamine, his data suggest, not a simple increase or decrease in their activity.