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The fact that addiction is a lifelong disease suggests that drug use has some kind of long-lasting effect on the brain that makes people vulnerable to relapse. But just what that is has been unclear.

Now, a preclinical study on cocaine use by a University at Buffalo research team reveals the genetic basis for relapse, beginning to explain how abstinence intensifies the craving for the drug over time.

Focusing on a center of reward and motivation in the brain, the researchers looked at molecules known as chromatin remodelers that can affect gene expression.

They found that a particular chromatin remodeler, called INO80, causes gene changes that enhance cocaine-craving behavior. While they found no change in expression of INO80 after one day of abstinence, they found a significant increase after 30 days. The researchers also zeroed in on a protein, TRIM3, that keeps INO80 in check by instructing it to degrade. A cocaine-induced decrease in TRIM3 likely underlies the observed increase in INO80: Less TRIM3 means more INO80, and more INO80 means more craving.

The researchers said they were inspired to address this question because the likelihood of relapse is so high even after long periods of abstinence. In society, they noted, this often gets unfairly cast as a personal failure.

“The focus of this work, and much of the work in my lab, is to understand how drugs of abuse like cocaine or heroin lead to long-lasting changes to the brain,” said , chair of the Department of Pharmacology and Toxicology at UB and senior author on the study. “This finding shines a light on the muddy waters of the neurobiology of addiction.”

The researchers emphasized that their work is allowing critical pieces of the addiction puzzle to fall into place—a key step, they said, toward finding therapeutic targets.