August 31, 2010

Preventing cocaine addiction relapse

Emory neuroscientists have identified how the drug disulfiram, used for years to deter alcoholics from drinking, can be effective against cocaine addiction as well. And they have shown that a newer drug with fewer side effects also prevents relapse.

The results were published online Aug. 25 by the journal Neuropsychopharmacology.

Disulfiram interferes with the body’s ability to metabolize alcohol, giving a fierce hangover to someone who consumes even a small amount.  In the 1990s, researchers were puzzled by disulfiram’s effectiveness in treating cocaine addiction, even though alcohol and cocaine affect the nervous system in different ways.

Disulfiram inhibits several enzymes in the body and can damage the liver, says geneticist David Weinshenker.

“We wanted to figure out how disulfiram was working so we could come up with safer and potentially more effective treatments,” he says.

In treating cocaine addiction, there are several challenges: not only getting people to stop taking the drug, but also preventing relapse. Cocaine boosts the levels of several neurotransmitters, including dopamine and norepinephrine, at the junctions between nerve cells by blocking the machinery the brain uses to remove them.

Cocaine “hijacks” the dopamine system, important for the sensation of pleasure produced by natural rewards such as food or sex. Similarly, norepinephrine has a role in attention and arousal, but its overactivation can trigger stress responses and relapse, he says.

Weinshenker’s team, including scientists from University of Georgia, showed that disulfiram prevents rats from seeking cocaine after a break, a model for addicts tempted to relapse. At the same time, it doesn’t stop them from taking cocaine when first exposed to it, or from enjoying their food.

Disulfiram appears to work by inhibiting dopamine beta-hydroxylase, an enzyme required for the production of norepinephrine. A dose of disulfiram that lowers the levels of norepinephrine in the brain by about 40 percent is effective, while doses that do not reduce norepinephrine have no effect on relapse-like behavior in rats.

To confirm that the beneficial effects of disulfiram were because of dopamine beta-hydroxylase inhibition, the researchers turned to a drug called nepicastat, which was originally developed for the treatment of congestive heart failure in the 1990s.

Nepicastat, a selective dopamine beta-hydroxylase inhibitor, was just as effective in preventing relapse-like behavior in rats. Its effectiveness against cocaine addiction is currently being tested in phase I clinical trials.

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