WSU researchers discover how a neural circuit drives relapse after opioid use

Washington State University researchers have discovered how a neural circuit – or a connection between two brain regions – drives relapse after opioid use, a finding that could lead to more effective treatments for opioid use disorders.

In a study published in the Journal of Neuroscience, researchers in the Department of Integrative Physiology and Neuroscience at WSU's College of Veterinary Medicine used a preclinical model to model opioid use in humans and found that reducing the activity within a specific neuronal circuit linking the prelimbic cortex and the paraventricular thalamus significantly reduced drug-seeking behavior. The project was led by graduate researcher Allison Jensen, the study's first author, working under assistant professor Giuseppe Giannotti.

While this study was done in rats, the same brain pathway exists in humans. We know people are going to use drugs, but for someone who decides, 'I'm done,' the challenge is stopping cravings. If we can target the brain regions driving those episodes, we can help prevent relapse and save lives."

Giuseppe Giannotti, assistant professor, Washington State University

Opioids are the leading cause of drug overdose deaths in the United States, accounting for more than 79,000 deaths in 2023. One of the major challenges for those trying to break opioid addiction is relapse. Studies show nearly 60% of people relapse within one week of completing an inpatient detoxification and as many as 77% relapse within six months after short-term inpatient care without medication-assisted treatment.

The paraventricular thalamus is known to play a central role in processing drug-associated cues and motivational states, but, importantly, the WSU researchers discovered that signals from the prelimbic cortex play a major role in activating the paraventricular thalamus. When the team reduced the activity of this brain pathway, heroin-seeking behavior dropped significantly.

"We wanted to know what makes the paraventricular thalamus respond so strongly to drug-associated cues," Jensen said. "By identifying the upstream driver of that response, we can begin to understand how cravings form and how to intervene."

To reduce activity in the brain pathway, the team used two approaches.

They first used chemogenetics, which involved introducing a designer receptor – a genetically engineered protein – into neurons of the prelimbic cortex sending projections to the paraventricular thalamus. Researchers could then activate the receptor with a specific drug that doesn't affect other cells, allowing them to reduce activity in the pathway, which was followed by a significant reduction in heroin-seeking behavior.

Even more promising was an optogenetic approach that used light to manipulate activity in the pathway. Researchers implanted a fiber-optic into the paraventricular thalamus to deliver a low-frequency light pattern that gradually desensitized the connection between the two brain regions and reduced the drive to seek heroin. This method was nearly twice as effective as the chemogenetic approach.

A similar approach called deep brain stimulation, in which electrodes deliver controlled electrical impulses to specific brain regions, could potentially achieve the same results in humans. Not only could it be effective for opioid addiction, Giannotti said, but it could also be adapted for other abused substances, including cocaine, alcohol and nicotine.

"These kinds of therapies could one day help reduce cravings in humans," Giannotti said. "If someone comes to a treatment facility, we could potentially use an approach like this to target this pathway and help them get through the periods when cravings are the highest."

The next step for Giannotti's lab is to examine how environmental cues – such as light and sounds associated with drug use – are dynamically activated in this brain circuit to drive relapse.

"Environmental cues can be incredibly powerful triggers of relapse in humans," Giannotti said. "Understanding the neuronal dynamics by which neurons respond to those cues will help us design even more precise and effective treatments."