Possible cocaine addiction trigger uncovered: Protein linked to mental retardation may be controlling factor in drug's effect in the brain

The study was published on August 15, 2010, in the journal Nature Neuroscience.

The results from the new study strongly suggest that a protein known as methyl CpG binding protein 2 (MeCP2) interacts with a type of genetic material known as microRNA to control an individual's motivation to consume cocaine.

"The study shows that MeCP2 blunts the amount by which microRNA-212 is increased in response to cocaine," said Paul Kenny, an associate professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "We have previously shown that miR-212 is very protective against cocaine addiction. Therefore, the conclusion is that MeCP2 may regulate vulnerability to addiction in some people through its inhibitory influence on miR-212. Without this influence, the expression of miiR-212 would be far greater in response to cocaine use, and the risk of addiction would likely be far lower."

This is the first time that MeCP2 has been shown to play a role in regulating cocaine addiction. Previously, the protein was most linked to Rett syndrome, a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females.

Interactions Shape Vulnerability

These new findings come on the heels of another cocaine addiction study by Kenny and his Scripps Florida colleagues published in the journal Nature in early July. That study showed for the first time that miR-212 -- a type of small non-protein coding RNA that can regulate the expression levels of hundreds or even thousands of genes -- influenced response to the drug in rats. Animals with increased miR-212 expression were less motivated to consume cocaine, pointing to the protective effects of miR-212 against cocaine addiction.

"The new findings are a significant advance from this previous study," Kenny said, "because they clearly demonstrate why microRNA-212 is not always fully protective -- because MeCP2 regulates by how much miR-212 levels will increase in response to cocaine. This suggests that our initial findings may be central to explaining the complex process of addiction, and understanding how miR-212 signaling is regulated will be important. This study adds another level of detail to the blueprint."

A major goal of drug abuse research is to understand why certain individuals make the switch from casual to compulsive drug use and develop into addicts. Periods of easy access to the drug, along with repeated overconsumption, can quickly trigger the emergence of addiction-like abnormalities in animal models.

In the new study, the scientists first looked at the expression of MeCP2 in the brain after exposure to cocaine. They found that expression was increased in those animals given extended access to the drug.

"At that point," Kenny said, "we wanted to know if this increase was behaviorally significant -- did it influence the motivation to take the drug?"

Using a virus to disrupt expression of MeCP2, the scientists found that rats consumed less and less cocaine. Intriguingly, levels of miR-212 were also far higher in those animals. Because increases in miR-212 suppress attraction to cocaine, the disruption of MeCP2, in essence, put miR-212 in charge and reduced vulnerability to the drug.

"We concluded that MeCP2 may play an important role in addiction by regulating the magnitude by which miR-212 expression is increased in response to cocaine," said Kenny. "In other words, MeCP2 seems to control just how much you can protect yourself against the addictive properties of cocaine."

Intriguingly, that was not the end of the story. In addition to MeCP2 blunting miR-212 expression, the scientists also found that the opposite was also true -- that miR-212 could in turn decrease levels of MeCP2. This suggests that both are locked together in a regulatory loop. Importantly, the two had opposite effects on the expression of a particular growth factor in the brain -- called BDNF -- that regulates just how rewarding cocaine is.

While the new study fills in an important piece of the puzzle, the Kenny lab is hard at work to further increase our understanding of addiction.

"We still don't know what exactly influences the activity levels of MeCP2 on miR-212 expression," Kenny said. "Now we plan to explore what drives it -- whether it's environmentally driven, and if genetic and epigenetic influences are important."

The study was supported by the National Institutes of Health, Ruth L. Kirschstein National Research Service Awards, and The National Alliance for Research on Schizophrenia and Depression.