Washington State University researchers have pinpointed a brain circuit that appears to drive opioid relapse and found ways to quiet it in rats, sharply reducing heroin-seeking behavior. The work could lay the groundwork for future brain-based treatments to help people get through the most intense periods of craving.
A team at Washington State University has identified a key brain circuit that appears to drive relapse after opioid use and found that dialing down its activity sharply reduced heroin-seeking behavior in rats.
The discovery, published in the Journal of Neuroscience, could help guide future treatments aimed at the brain itself to help people stay off opioids during the most vulnerable periods after they stop using.
Opioids remain the leading cause of drug overdose deaths in the United States, responsible for more than 79,000 deaths in 2023. Even when people complete detox or short-term treatment, relapse is common, especially in the first days and weeks.
The WSU researchers focused on a connection between two brain regions: the prelimbic cortex, which is involved in decision-making and control, and the paraventricular thalamus, a hub that processes drug-related cues and motivational states.
The paraventricular thalamus was already known to respond strongly to sights, sounds and other cues linked to drug use. The new study shows that signals coming from the prelimbic cortex are a major driver of that response.
First author Allison Jensen, a graduate researcher, said the team wanted to understand why this thalamus region reacts so powerfully when an animal encounters drug-associated cues.
“We wanted to know what makes the paraventricular thalamus respond so strongly to drug-associated cues,” Jensen, who led the research under Giuseppe Giannotti, an assistant professor in the College of Veterinary Medicine, said in a news release. “By identifying the upstream driver of that response, we can begin to understand how cravings form and how to intervene.”
In one set of experiments, the researchers used chemogenetics, a technique that introduces a specially engineered receptor into targeted neurons. The receptor can be switched on with a drug that does not affect other cells, allowing researchers to turn down activity in a single pathway.
When the WSU team used chemogenetics to dampen the prelimbic-to-thalamus connection, heroin-seeking behavior dropped significantly.
In a second set of experiments, they turned to optogenetics, which uses light to control genetically sensitized neurons. The researchers implanted a fiber-optic cable into the paraventricular thalamus and delivered a low-frequency light pattern to the incoming fibers from the prelimbic cortex. Over time, this light pattern weakened, or desensitized, the connection between the two regions and reduced the drive to seek heroin.
This optogenetic approach was nearly twice as effective as the chemogenetic method at cutting heroin-seeking behavior in the animals.
Giannotti emphasized that the work was done in rats but targets a circuit that also exists in people.
“While this study was done in rats, the same brain pathway exists in humans,” he said in the news release.
That overlap raises the possibility that future brain-based therapies could one day modulate this pathway in patients with opioid use disorder. One candidate is deep brain stimulation, a technique already used for conditions such as Parkinson’s disease and some forms of epilepsy. In deep brain stimulation, electrodes deliver controlled electrical pulses to specific brain regions.
Giannotti noted that such an approach might eventually be adapted for other addictive substances, including cocaine, alcohol and nicotine.
“These kinds of therapies could one day help reduce cravings in humans,” Giannotti added. “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 study the role of environmental cues — such as a familiar street corner, a certain song or the sight of drug paraphernalia — in triggering 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.”
For now, the findings are an early but important step. They do not translate directly into a new therapy, but they give scientists a clearer map of the brain circuitry that underlies opioid craving and relapse.
By showing that weakening a specific pathway can sharply reduce drug seeking in animals, the WSU team has identified a promising target for future interventions — and offered a measure of hope that more effective, brain-based tools to fight opioid addiction may be on the horizon.
Source: Washington State University