Researchers at Scripps Research have shown in an animal model that the brain learns to pursue alcohol as a way to find relief, rather than only for its rewarding effects.
What drives a person to keep drinking alcohol despite the harm it causes to their health, relationships, and overall well-being? New research from Scripps Research points to a possible answer: a small midline brain region helps shape how animals learn to drink in order to relieve the stress and discomfort of withdrawal.
In a study recently published in Biological Psychiatry: Global Open Science, the Scripps Research team examined brain activity in the paraventricular nucleus of the thalamus (PVT) in rats. They discovered that when rats linked environmental cues with alcohol’s ability to ease withdrawal symptoms, activity in this brain region increased, reinforcing relapse behaviors.
By uncovering this pathway, the study highlights one of addiction’s most persistent aspects—using alcohol not for enjoyment but to avoid suffering—and may pave the way for new therapies for substance use disorders (SUDs) and related conditions such as anxiety.
“What makes addiction so hard to break is that people aren’t simply chasing a high,” says Friedbert Weiss, professor of neuroscience at Scripps Research and senior author of the study. “They’re also trying to get rid of powerful negative states, like the stress and anxiety of withdrawal. This work shows us which brain systems are responsible for locking in that kind of learning, and why it can make relapse so persistent.”
“This brain region just lit up in every rat that had gone through withdrawal-related learning,” says co-senior author Hermina Nedelescu of Scripps Research. “It shows us which circuits are recruited when the brain links alcohol with relief from stress—and that could be a game-changer in how we think about relapse.”
From behavior to brain maps
About 14.5 million people in the United States are estimated to have alcohol use disorder, a condition that includes a spectrum of harmful drinking behaviors. Similar to other forms of substance addiction, it is marked by recurring cycles of withdrawal, abstinence, and relapse.
In 2022, researchers Weiss and Nedelescu investigated these processes in rats to better understand how learning shapes addiction in the brain. At the outset, the animals linked alcohol with pleasurable effects and were motivated to drink more. But as they went through repeated periods of withdrawal and relapse, the drive to drink became much stronger. Once the rats learned that alcohol could relieve the distress of withdrawal—an example of negative reinforcement, or the easing of a “negative hedonic state”—they pursued alcohol more intensely and continued seeking it even in challenging conditions.
“When rats learn to associate environmental stimuli or contexts with the experience of relief, they end up with an incredibly powerful urge to seek alcohol in the presence of that stimuli –even if conditions are introduced that require great effort to engage in alcohol seeking,” says Weiss. “That is, these rats seek alcohol even if that behavior is punished.”
In this study, the researchers set out to identify the specific networks of brain cells that drive the learning process in which environmental cues become linked to the relief of a negative hedonic state.
Using advanced whole-brain imaging in rats, they analyzed cellular activity to determine which regions became more responsive to alcohol-associated cues. Four groups of rats were compared: one group that had experienced withdrawal and learned that alcohol reduced a negative hedonic state, and three separate control groups that had not developed this association.
Although multiple brain regions showed heightened activity in the withdrawal-experienced group, one region in particular stood out: the paraventricular nucleus of the thalamus (PVT), a structure already recognized for its involvement in stress and anxiety.
“In retrospect, this makes a lot of sense,” says Nedelescu. “The unpleasant effects of alcohol withdrawal are strongly associated with stress, and alcohol is providing relief from the agony of that stressful state.”
The researchers hypothesize that this negative hedonic state, and the activation of the PVT in the brain as a response, is critical for how the brain learns and perpetuates addiction.
A better understanding of addiction
The implications of the new study extend well beyond alcohol, the researchers say. Environmental stimuli conditioned to negative reinforcement—the drive to act in order to escape pain or stress—is a universal feature of the brain, and can drive human behavior beyond substance use disorders such as anxiety disorders, fear-conditioning and traumatic avoidance learning.
“This work has potential applications not only for alcohol addiction, but also other disorders where people get trapped in harmful cycles,” says Nedelescu.
Future research will zoom in even further. Nedelescu and colleagues at Scripps Research want to expand the study to females and to study neurochemicals released in the PVT when subjects encounter environments associated with the experience of this relief from a negative hedonic state. If they can pinpoint molecules that are involved, it could open new avenues for drug development by targeting those molecules.
For now, the new study underscores a key shift in how basic scientists think about addiction.
“As psychologists, we’ve long known that addiction isn’t just about chasing pleasure—it’s about escaping those negative hedonic states,” says Weiss. “This study shows us where in the brain that learning takes root, which is a step forward.”
Reference: “Recruitment of Neuronal Populations in the Paraventricular Thalamus of Alcohol-Seeking Rats With Withdrawal-Related Learning Experience” by Hermina Nedelescu, Elias Meamari, Nami Rajaei, Alexus Grey, Ryan Bullard, Nathan O’Connor, Nobuyoshi Suto and Friedbert Weiss, 5 August 2025, Biological Psychiatry Global Open Science.
DOI: 10.1016/j.bpsgos.2025.100578
This work was supported by funding from the National Institutes of Health (Ruth L. Kirschstein Institutional National Research Service Award T32AA007456, K01 DA054449, R01 AA027555, and R01 AA023183).
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2 Comments
So what are you supposed to do when your in a stressful state
Use mindfulness and CBT