Altered stress signaling helps explain relapse in alcohol use disorder

A new study by Scripps Research reveals that alcohol dependence disrupts two signaling pathways in a stress-related part of the brain-and offers insights on developing drugs to treat this condition.

The research, conducted in animal models and published in Frontiers in Pharmacology on November 26, 2025, helps explain why people with alcohol use disorder (AUD) struggle to stay sober, especially under stress.

"We think that alcohol dependence changes these systems, and that's why individuals are prone to seek out alcohol even if they've gone without it for some time," says senior author Rémi Martin-Fardon, an associate professor in the Department of Translational Medicine.

AUD, a condition in which someone cannot control their drinking despite the harm it causes, affects nearly 28 million Americans. FDA-approved medications like naltrexone, which reduces cravings, exist but have significant drawbacks, including nausea, and they do not work for everyone.

This recent study points to potential new treatments by uncovering molecular changes in two signaling systems-orexin and dynorphin-and the unexpected effects of blocking them. Inhibiting either signal individually reduced relapse-like behavior but, interestingly, blocking both cancelled this protective effect.

Once someone loses control of their drinking, regaining it can be a lifelong struggle. Research has demonstrated that stress increases the likelihood someone will become dependent on alcohol and will relapse after they try to stop. But the relationship goes two ways, because drinking itself activates the body's stress response systems. 

Among the systems affected is orexin-dynorphin signaling. These two neuropeptides are released by the same neurons, which originate in the brain's hypothalamus, the region that coordinates the release of chemical signals. In normal brains, they have opposing effects: Orexin, discovered by scientists at Scripps Research and another team in 1998, acts as a "go" signal and promotes drug-seeking behavior. Meanwhile, dynorphin serves as the "stop" signal. In AUD, excessive drinking appears to alter dynorphin signaling so it produces the many diverse and unpleasant feelings that accompany withdrawal and motivate continued drinking. 

Martin-Fardon's group has previously studied this relationship in cocaine addiction. This time, in experiments led by postdoctoral researcher Francisco Flores-Ramirez with research assistant Glenn Pascasio, they turned to alcohol.

The team zeroed in on a small region within the brain's thalamus called the posterior paraventricular nucleus of the thalamus, or pPVT, a stress-processing hub that receives orexin and dynorphin signals. Martin-Fardon's earlier work indicated that the pPVT is key to stress-triggered relapse-like behavior.

In this study, they found telling changes in gene expression. In alcohol-dependent rats, the hypothalamus appeared to be ramping up production of both the orexin "go" and dynorphin "stop" signals. But the pPVT's ability to receive them was skewed. Its neurons expressed fewer receptors for orexin, but more for dynorphin.

"What that tells us is that just being dependent on alcohol changes the orexin and dynorphin system, and that these changes persist well into abstinence," Flores-Ramirez says.

To reach these conclusions, the team simulated AUD in male rats, which pressed a lever to receive alcohol. After cutting off the alcohol supply, the researchers examined gene expression in both the pPVT and hypothalamus. Some animals had received inhibitors to block orexin or dynorphin signaling in their pPVTs, producing complex and somewhat counterintuitive results. As expected, shutting down the orexin "go" signal reduced stressed rats' attempts to drink alcohol. But blocking dynorphin's "stop" signal also appeared to significantly decrease the relapse-like behavior. When they inhibited both signals together, however, the rats pressed the lever as if they had not received any inhibitor at all.

Because the study focused on a single brain region and relied solely on male animals, the researchers say it's difficult to explain these effects or tie them directly to the changes in gene expression. Still, they sound a note of caution for drug development.

"If you want to combine treatments, you have to be very careful," Martin-Fardon says, though he notes that this strategy may be effective with different inhibitors-perhaps taking advantage of existing drugs or compounds with similar chemistry.

His team is now collaborating with Scripps Research colleagues Edward Roberts and Hugh Rosen, who are developing selective, shorter-acting dynorphin signaling inhibitors intended to provide quick relief. Martin-Fardon is also interested in combining one of these compounds with suvorexant, an insomnia drug that blocks orexin signaling, or a similar drug.