July 19, 2010

Tiny RNA Molecule in the Brain Curbs Cocaine Use

Illustration of a head with a DNA strand in place of the brain

Scientists have identified a microRNA, a tiny snippet of genetic material, that may suppress cocaine-seeking behavior. The finding suggests an entirely new approach for treating drug abuse and addiction.

Cocaine use triggers a variety of structural and functional adjustments to the brain's reward system. The changes can have a dual effect. In both humans and rats, the alterations can boost drug-seeking behavior and lead to uncontrollable intake. At the same time, long-term consumption lessens the response to cocaine, which can blunt the motivation to use it. Researchers suspect that these differing influences may be why only about 15% of cocaine users ultimately lose control and compulsively seek the drug.

MicroRNAs are small pieces of RNA that don't code for proteins. Instead, they regulate how much of a protein is made. Over the past decade, microRNAs have been linked to various cancers, degenerative disorders and other conditions. But the tiny molecules' contributions to drug use and addiction have come under scrutiny only recently.

A research team lead by Dr. Paul J. Kenny of the Scripps Research Institute in Jupiter, Florida, decided to explore how brain levels of specific microRNAs change when rats have extended or limited access to cocaine. The study was funded by NIH's National Institute on Drug Abuse (NIDA).

In the July 8, 2010, issue of Nature, the scientists report that rats given 6 hours of extended access to cocaine each day had markedly increased levels of a molecule called microRNA-212 in a particular brain region. The levels were nearly double those in rats with access to cocaine for an hour or less daily. The brain region, called the dorsal striatum, helps to regulate the development of habit formation.

The researchers next tested the effects of elevated microRNA-212. They used a genetically altered virus to boost microRNA-212 expression in the dorsal striatum. A control group received an "empty" virus. When given extended access to cocaine, both groups predictably escalated their intake. But over time, cocaine intake plummeted in the rats with elevated microRNA-212. Cocaine consumption in this group continued to drop even as their exposure to the drug increased. Their cocaine intake became so low that they seemed to have a growing dislike for the drug.

In contrast, when the researchers blocked the action of microRNA-212 in the brain, cocaine intake increased sharply, and the rats began to self-administer the drug at exaggerated rates, similar to compulsive drug users. These results suggest that microRNA-212 may play an important role in preventing out-of-control drug use.

"The results of this study offer promise for the development of a totally new class of anti-addiction medications," says Kenny. "Because we are beginning to map out how this specific microRNA works, we may be able to develop new compounds to manipulate the levels of microRNA-212 therapeutically with exquisite specificity, opening the possibility of new treatments for drug addiction."

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