How cocaine rewires the brain to drive relapse

(Press-News.org) When a cocaine addict relapses, it isn’t a matter of personal failure — it’s the biological result of their brain’s rewiring, new research finds.

Michigan State University scientists found that cocaine changes how the hippocampus functions, contributing to the ongoing compulsion to seek out the drug. Their National Institutes of Health-supported research, published in Science Advances, not only explains why cocaine addiction is notoriously difficult to treat, but it could also help scientists develop new pharmaceutical therapies.

“Addiction is a disease in the same sense as cancer,” said senior author A.J. Robison, a professor of neuroscience and physiology. “We need to find better treatments and help people who are addicted in the same sense that we need to find cures for cancer.”

At least a million people nationwide struggle with cocaine addiction, and right now, there’s no FDA-approved medication to treat it. People who stop using don’t experience the same physical withdrawal symptoms that opiates cause, but that doesn’t mean it’s easy to quit. The drug hijacks the brain, flooding the reward centers with dopamine. This positive reinforcement tricks the brain into feeling like it’s doing something good instead of destructive.

Even if someone successfully quits, the odds aren’t in their favor. About 24% relapse to weekly use, and another 18% return to a treatment program within a year.

Andrew Eagle, a former postdoctoral researcher in Robison’s lab and the paper’s lead author, found a key player responsible for the compulsion — a protein called DeltaFosB. He used a specialized form of CRISPR technology to examine the role this protein plays in specific brain circuits when mice were exposed to cocaine.

Using mouse models, he learned that this protein acts like a switch, turning genes on and off in the circuit between the brain’s reward center and the hippocampus, the brain’s memory hub. The longer someone uses cocaine, the more this protein accumulates in the circuit. This protein changes how the neurons function, altering how the circuit responds to cocaine.

“This protein isn’t just associated with these changes, it is necessary for them,” Eagle said. “Without it, cocaine does not produce the same changes in brain activity or the same strong drive to seek out the drug.”

The research team also found another group of genes controlled by DeltaFosB after chronic cocaine use. One of those genes, called calreticulin, helps regulate how neurons communicate with each other. Their work showed calreticulin contributes to revving the brain’s engine to compulsively seek out more cocaine.

These findings in mouse models could have direct applications to humans, which share many of the same genes and similar circuits. Robison’s lab is partnering with researchers at the University of Texas Medical Branch in Galveston, Texas, to create compounds that target DeltaFosB. Together, they have a grant from the National Institute of Drug Abuse to develop and test compounds that regulate DeltaFosB’s ability to bind to DNA.

“If we could find the right kind of compound that works in the right way, that could potentially be a treatment for cocaine addiction,” Robison said. “That’s years away, but that’s the long-term goal.”

Next, Robison’s lab will examine how hormones impact these brain circuits, and whether cocaine affects the male and female brain differently. This work could help explain biological differences in addiction risk between men and women.

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