Brain-Protein Finding Gives Clues to Cocaine Addiction

New discoveries about a regulatory protein called methyl CpG binding protein 2 (MeCP2) in the brains of rats have deepened scientists' understanding about the mechanisms underlying addiction.

Findings from a new study show that the protein increases rats' motivation to self-administer cocaine and likely interacts with genetic material found to have the opposite effect to regulate drug intake and addiction.

The study results appeared in the August 15 Nature Neuroscience.

Researchers at the Scripps Research Institute in Jupiter, Fla., found that rats who had longer periods of access to cocaine (six hours a day for a week) had increased levels of MeCP2 in the dorsal striatum of their brains, compared with rats who had restricted access to the drug (one hour a day for a week). As levels of MeCP2 increased, so did rats' propensity to self-administer cocaine.

Mutations in the gene for MeCP2 are responsible for a progressive genetic neurodevelopmental disorder called Rett syndrome, which is the most common cause of mental retardation in females. As part of the study, Paul Kenny, Ph.D., and colleagues also found that MeCP2 may interact with a type of genetic material known as microRNA to regulate and control cocaine consumption.

The findings suggest that the protein “may play a central role in driving the increasing motivation to consume the drug during the development of addiction,” Kenny told Psychiatric News. Kenny is an associate professor in the Laboratory of Behavioral and Molecular Neuroscience in the Department of Molecular Therapeutics at the Scripps Research Institute.

To investigate the role of MeCP2 in the regulation of cocaine intake, Kenny and his colleagues developed a virus that would reduce the levels of MeCP2 in the brains of two groups of six rats each. Two other groups of six rats each were injected with a control virus that did not alter MeCP2 levels. Among the rats that received the virus used to block MeCP2 expression, one group was permitted six hours of access to cocaine each day for 10 days, and the other was allowed only one hour of cocaine access a day for 10 days.

The researchers also divided the rats that received a control injection into long- and short-access groups.

They found that among rats that had restricted access to cocaine each day (one hour), self-administration or intake was about the same between rats with blocked MeCP2 and those that had normal expression of the protein in their brains.

However, among the rats with extended periods of access to cocaine, those that received the MeCP2 “knock-down” injection had markedly decreased cocaine intake compared with that received the placebo (p<0.0001).

Genetic Material Alters Effect

In a related report in the July 8 Nature, Kenny's group reported that MiRNA-212, a nonprotein coding RNA that has the potential to regulate the expression of thousands of genes, had the opposite effect of MeCP2 on rats—it lessened their self-administration of the drug over time. To find out how MeCP2 and MiRNA-212 might work in tandem to regulate cocaine intake in rats, Kenny and his colleagues measured levels of MiRNA-212 in rats that received the virus that knocked down or blunted the expression of MeCP2 and found that levels of MiRNA-212 were far higher in these rats than in the ones that received the control “virus” (p<0.0001), suggesting that MeCP2 acts to blunt the increased expression of protective MiRNA-212 in response to cocaine.

Because higher levels of MiRNA-212 seemed to dampen rats' compulsion to self-administer cocaine, the blocking of MeCP2 resulted in a far greater protective action of MiRNA-212 in those rats. When researchers disrupted the signaling of MiRNA-212 in one group of rats, they found that cocaine use subsequently increased in those in the condition that included extended periods of access (p<0.005).

‘Locked in Regulatory Loop’

Kenny described MiRNA-212 and MeCP2 as being “locked in a regulatory loop” in which MeCP2 blunts the expression of the genetic material, and, in turn, the MiRNA-212 has the power to lessen levels of MeCP2 in the dorsal striatum. Therefore, it is likely that the balance between these two signaling agents determines vulnerability to the addictive effects of cocaine.

Further research will seek to elucidate the interaction between the genetic material and the regulatory protein and the extent to which environment and genetic influences play a role, Kenny said.

An abstract of “MeCP2 Controls BDNF Expression and Cocaine Intake Through Homeostatic Interactions With MicroRNA-212” is posted at <www.nature.com/neuro/journal/v13/n9/full/nn.2615.html>.