In 2017, the U.S. Department of State revealed that American cocaine use and availability was on the rise for the first time in nearly a decade. It was bad news for public health officials, who are well aware that there are no medications approved by the U.S. Food and Drug Administration to treat the powerful addiction it causes. In an attempt to find a new way to treat this public health concern, scientists recently examined genes throughout the brain, pinpointing the ones most likely to be altered by addiction.

Previous studies have focused on specific genes, a singular brain region, or just one aspect of cocaine addition. But this study, published Thursday in Biological Psychiatry, looked at changes in gene expression in the entire brain, identifying genetic changes in six regions linked to the brain’s reward circuitry caused by cocaine use. The extent of these changes, they write, is directly related to how long the drug has been taken.

“Our study is the first to identify gene expression changes throughout the brain and across the ‘life cycle’ of addiction in an unbiased matter,” study co-author and Icahn School of Medicine at Mount Sinai postdoctoral fellow Deena Walker, Ph.D. tells Inverse. “In other words, we investigated all genes expressed in the brain, not a subset thought to be important for addiction.”

lab mouse
Mice were divided into three groups: one-time cocaine users, addicts in withdrawal, and relapsed users.

The expression of any gene can increase or decrease, depending on changing conditions. In this case, Walker’s team wanted to find out which genes in the brain are more or less active during a state of cocaine addiction. The hope is that identifying those genes would help scientists find a way to reverse the effects of addiction, as they manifest on a molecular level.

So, they compared brains from a control group of mice to those from mice who had self-administered cocaine. Some of the mice were examined after 24 hours of cocaine use, others after a 30-day period of withdrawal, and some after they were re-exposed to cocaine after the drug-free 30 days. The brains of the mice were dissected rapidly and frozen on dry ice after their time with cocaine was done.

blood, mouse
The left shows mouse brain blood vessels before cocaine, the right is after cocaine use.

To examine the six interconnected brain reward regions, the team used RNA sequencing and an analytic method meant to examine patterns of gene expression in the brain, which allowed them to identify genes associated with addiction-related behaviors as well as the potential upstream regulators of those genes. Regulators are genes that control whether another gene becomes actively expressed or not; think of them like a light switch for a DNA bulb.

This analysis showed that many “predicted transcriptional regulators were consistent across patterns and brain regions,” the researchers write. In other words, the same light switches seemed to be involved in all the regions they were interested in.

“This is significant because each gene list is unique for a pattern within a brain region, suggesting that the targets of these predicted regulators change depending on cocaine history and re-exposure.”

Cocaine, molecular structure
The molecular structure of cocaine.

“By looking for genes that changed in the same direction across all brain regions and were associated with addiction related behaviors, we were able to identify genes that might serve as novel therapeutic targets in humans addicted to cocaine,” says Walker. “Ideally, the molecules we identified might serve as targets for treatment of addiction by prevent relapse after treatment in an addiction program.”

As the first study of its kind to identify transcripts that are changing in multiple brain regions, it serves as a window to what is going on when an individual begins using cocaine, experiences withdrawal, and goes back to using the drug. One of the biggest challenges of addiction is preventing relapse after treatment, and if scientists know which genes to target with drugs in order to squash that addiction, they might be able to prevent relapse.

Walker says that now the team is in the process of determining what happens when these potential regulators of gene expression are manipulated, with the goal of blocking addiction-related behaviors.

“However, the data is publicly available,” says Walker, “and we believe that this rich dataset will serve as a valuable resource for the entire field and hope it will be mined by other laboratories to identify other novel therapies for addiction.”