Scientists find brain circuit that traps alcohol users in the vicious cycle of addiction

Published on August 5, 2025, in Biological Psychiatry: Global Open Science, the study focused on a cluster of neurons in the paraventricular nucleus of the thalamus (PVT) in rats. The researchers found that this brain area became increasingly active and strongly promoted relapse when rats linked environmental cues with the relief that alcohol provided from withdrawal symptoms. By uncovering this pathway, the study highlights one of addiction's most persistent features -- drinking not for enjoyment, but to avoid emotional and physical pain -- and may pave the way for new treatments 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

In the United States, an estimated 14.5 million people struggle with alcohol use disorder, which includes a range of harmful drinking behaviors. Like other substance addictions, alcohol dependence involves repeated cycles of withdrawal, abstinence, and relapse.

In a 2022 study, Weiss and Nedelescu explored how the brain learns during these cycles using rats as a model. Early on, the animals associated alcohol with pleasure and sought more. But as they experienced repeated withdrawal and relapse, their motivation became much stronger. After realizing that alcohol eased withdrawal discomfort -- a form of negative reinforcement, or relief from a "negative hedonic state" -- the rats persistently pursued alcohol even when faced with aversive or punishing 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 the new study, the team aimed to identify which neural networks were responsible for learning to connect environmental cues with relief from this negative emotional state.

Using advanced whole-brain imaging, the researchers mapped cellular activity in rats exposed to alcohol-related cues. They compared four groups: one that had learned through withdrawal that alcohol relieves a negative hedonic state, and three control groups that had not experienced this learning.

Although several brain regions showed elevated activity, one stood out -- the PVT, a region already known for its role in stress and anxiety regulation.

"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 team proposes that this negative hedonic state, and the resulting activation of the PVT, may play a crucial role in how the brain learns and reinforces addictive behaviors.

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."

In addition to Weiss and Nedelescu, authors of the study, "Recruitment of Neuronal Populations in the Paraventricular Thalamus of Alcohol Seeking Rats with Withdrawal-related Learning Experience," are Elias Meamari, Nami Rajaei, Alexus Grey, Ryan Bullard, and Nobuyoshi Suto of Scripps; and Nathan O'Connor of MBF Bioscience.

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).