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Aug 16, 2010

Regulatory Loop for Cocaine Addiction Uncovered

  • A regulatory protein known for its role in Rett syndrome may also play a critical role in cocaine addiction, report scientists at the Scripps Research Institute and Duke University Medical Center. Furthermore, studying rats, they found the protein, which is called methyl CpG binding protein 2 (MeCP2), interacts with an miRNA known as miR-212 to control the animal’s motivation to consume cocaine.

    The research appears in Nature Neuroscience in a paper titled “MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212.” Research linking miR-212 to cocaine intake was published by the same Scripps team in a July Nature paper.

    When MeCP2 is mutated or missing, symptoms of the neurodevelopmental disorder Rett syndrome arise, causing a gradual loss of brain function during early development. This fact led Duke University Medical Center researchers to test a theory that the protein might also contribute to synapse changes in a fully formed adult mouse brain when exposed to psychostimulant use.

    In two experiments with mice, Anne West, M.D., Ph.D., an assistant professor of neurobiology, and colleagues found that virally manipulating levels of MeCP2 in the brains of adult mice affected their place preference, a measure of the rewarding properties of the amphetamines the mice consumed in that location.

    These studies also showed that MeCP2 is involved in the process through which repeated amphetamine use changes both the structure and the function of the brain, according to Dr. West. "MeCP2 is a transcriptional regulator that responds to an extracellular stimulus like an amphetamine, and we showed that it can modulate synapses in the part of the brain (nucleus accumbens) that is responsible for reward.”

    Additionally, the scientists 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. Using a virus to disrupt expression of MeCP2, it was found that rats consumed less and less cocaine, according to the Scripps team led by Paul Kenny, Ph.D., an associate professor in the department of molecular therapeutics. 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.

    The results suggest that the brain's balance between MeCP2 and miRNA-212 ultimately regulates cocaine intake. "The study shows that MeCP2 blunts the amount by which microRNA-212 is increased in response to cocaine," explains Dr. Kenny.

    In addition to MeCP2 suppressing 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.

    "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 miR-212 would be far greater in response to cocaine use, and the risk of addiction would likely be far lower.

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


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