Protein regulator shows promise against addiction

Little things can make a big difference in the brain. Case in point: A tiny snippet of RNA may help guard cocaine-using rats against addiction to the drug, a new study shows.

The minuscule molecular guard is a hairpin-shaped piece of RNA known as a microRNA. Raising levels of a microRNA called miR-212 in the brains of cocaine-using rats led the animals to take less of the drug than rats with normal microRNA levels, researchers report in the July 8 Nature. Similarly, blocking the microRNA’s action increased the rats’ cocaine use.

If the results hold true in people, researchers may be able to develop new therapies for treating addiction to cocaine and other drugs of abuse. “Once you get out of whack, this is something that might help bring you back,” says Yale neuroscientist Marina Picciotto, who was not involved in the study.

It’s unlikely that the research will lead to gene therapy to raise levels of microRNAs in people’s brains. But small-molecule drugs that mimic the microRNA’s action might be helpful.

Just 21 to 23 RNA units long, microRNAs are major regulatory molecules (SN: 3/1/08, p. 136) that govern part of the process by which instructions contained in DNA are transformed into proteins. The molecules generally block protein production. So it was a surprise to find levels of a protein called CREB increase with rising levels of miR-212, says Paul Kenny, a neuroscientist at the Scripps Research Institute in Jupiter, Fla.

CREB has been found to help fight addiction (SN: 5/24/08, p. 14) by decreasing the rewarding experience of taking cocaine, sometimes to the point that rats actually develop an aversion to the drug. It took Kenny and his colleagues years to work out exactly how cocaine use boosts miR-212 production and how the microRNA, in turn, increases production of CREB protein. The process involves several steps and intermediate proteins, including a protein called Raf1 that had never before been shown to be involved in the response to drugs.

The miR-212 microRNA blocks an inhibitor of Raf1 in the striatum, a part of the brain involved in learning habits like driving a car and learning to avoid making the same mistake twice. With its inhibitor in check, Raf1 is free to stimulate CREB production, Kenny and his colleagues show in the new study.

Protecting against cocaine addiction may be a side benefit of mir-212’s normal job of regulating CREB production and other biochemical processes in the brain, Kenny says. The microRNA helps set the correct level of CREB production to keep it from getting too low, which leads to addiction and anxiety, or too high, which leads to depression.

Any therapy targeting CREB would have to strike this delicate balance as well, he says. “Obviously there could be some very profound side effects,” Kenny says.

The researchers are investigating how mir-212 is regulated and whether it is protective against addiction to other drugs, such as nicotine and alcohol.