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Two Studies Associate microRNAs with Cocaine Addiction

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By Doug Macron

Amid the mounting evidence linking microRNAs to conditions ranging from cancer to cardiovascular disease, two new reports published this month suggest that small, non-coding RNAs also play a key part in cocaine addiction.

The first paper, which appeared this week in The Journal of Experimental Medicine, provided evidence for the role of miRNAs in cocaine addiction by demonstrating that a deficiency in a protein necessary for miRNA generation and gene silencing reduced the desire of mice to self-administer the drug.

In the second, which was published in Nature, researchers described the discovery that one particular miRNA influences the motivational properties of cocaine.

In JEM, investigators from Rockefeller University, in collaboration with colleagues from the Scripps Research Institute, Aarhus University, and the European Molecular Biology Laboratory, aimed to follow up on research from another group finding that miRNAs may target genes involved in cocaine addiction by taking advantage of the importance the Argonaute 2 protein in the function of the ncRNAs.

While the four Argonaute genes in humans and mice encode four different proteins that are "structurally and functionally similar … only Ago2 is able to control mRNA expression by slicing of mRNAs that are fully complementary to specific miRNAs," the team wrote in the JEM paper.

In addition, Ago2 contributes to the generation of a limited number of miRNAs from their precursors, which "provides an opportunity to relate physiological changes caused by Ago2 deficiency to expression changes of specific miRNAs in various cell types, including neurons."

As such, the researchers used Ago2-deficient mice to examine the potential involvement of miRNAs in cocaine addition, finding that ablation of the protein "alleviates" cocaine addiction as measured by the animals' motivation to self-administer the drug in their home-cage environment.

They specifically found that ablation of Ago2 in dopamine receptor 2-expressing neurons leads to a "significant decrease of daily cocaine self-administration" in mice compared to controls. "Furthermore, characterization of the cocaine dose-response curve revealed a profound downward shift of the … curve … [which is] considered as a decrease in the motivation to consume cocaine."

In the end, the researchers posit that Ago2's role in cocaine addiction is tied to the function of Ago2-dependent miRNAs, which include those enriched in dopamine receptor 2-expressing neurons and those that are enriched and also induced by cocaine administration.

They further speculate that those miRNAs that are induced by cocaine administration "play a crucial role in development of addiction." Predicted targets of these miRNAs, they noted, include cocaine-induced neuronal plasticity genes.

These findings "provide a foundation for future studies that will identify the contribution of individual … miRNAs to various facets of addictive behavior in mice and possibly humans," they concluded.

Such work, it seems, is already underway.

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Earlier this month, Scripps researchers detailed how miR-212 protects against compulsive cocaine intake in rats by amplifying the activity of an established negative regulator of cocaine reward.

While structural and functional modifications such as alterations to brain reward systems are believed to increase sensitivity to cocaine's motivation effects, recent data suggest the drug also triggers reductions in users' responsiveness to it, resulting in over-consumption, they wrote in Nature.

"Considering the complexity of cocaine-induced neuroadaptive responses in brain reward systems, it is likely that highly synchronized programs of gene regulation are involved," the researchers stated.

According to Scripps researcher Paul Kenny, who is a senior author on the paper, the fact that miRNAs "can regulate networks of genes [make them] very attractive from the standpoint of complex disorders, particularly psychiatric disorders, which can have many simultaneous deficits in multiple signaling cascades and pathways important for brain function."

And because drug abuse is a "very complex disorder, we figured microRNAs may play a role," he told Gene Silencing News this week.

In Nature, the Scripps team notes that the dorsal striatum is a "key brain region regulating the development of compulsive cocaine use, and expression profiling has revealed that miR-212 and the closely related miR-132 are both up-regulated in this part of the brain in rats with access to self-administered cocaine.

The researchers examined rats that had been treated with a lentiviral vector that over-expressed miR-212 and rats treated with a control vector, and found that cocaine intake did not differ among animals with restricted access to the drug. However, intake in rats treated with the miR-212 lentivirus became "progressively lower" compared with control animals when they had extended access to cocaine.

Further, rats treated with a locked nucleic acid that inhibited miR-212 experienced increased cocaine intake when access to the drug was not restricted. Administration of an LNA against an unrelated miRNA, miR-1, had no effect on cocaine intake.

The investigators determined that miR-212 modulates cocaine intake by "markedly amplifying" the activity of CREB, which has been shown to decrease the rewarding effects of the drug. "This action occurs through Raf1-mediated sensitization of adenylyl cyclase activity and increased TORC expression," they wrote.

"Striatal miR-212 therefore protects against development of compulsive drug taking, and factors that regulate miR-212 signaling may have key roles in determining vulnerability to cocaine addiction," they added. "Hence, miRNAs are important molecular regulators that control the complex actions of cocaine in brain reward circuitries and the neuroadaptations associated with addiction."

Still, questions remain to be answered, Kenny noted. Among these is why the protective effect of miR-212 against cocaine over-consumption isn't complete.

"That led us on a quest to try to understand better how microRNA expression is regulated in response to cocaine, and whether there are pro-addiction mechanisms that may control [their] expression," Kenny added.

He noted that his lab has recently had a paper accepted for publication showing that there are "transcriptional repressors that are simultaneously activated in response to cocaine, and they can increase vulnerability to cocaine abuse, in part, by blunting the responsiveness" of miR-212.