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

In a new study, published in Biological psychiatry: global open science On August 5, 2025, a Scripps Research team knocked down a group of brain cells in the hypothalamic nucleus (PVT) in mice. They found that this area becomes more active, leading to strong relapse behavior, when mice learn to associate environmental stimuli with relief of withdrawal symptoms by alcohol. By illuminating this brain pathway, the research sheds light on one of the most stubborn traits of addiction – drinking not for pleasure, but to escape pain – and could ultimately lead to new treatments for substance use disorders (SUDs) as well as other uncontrollable behaviors including anxiety.

“What makes addiction so difficult is that people don’t simply chase,” says Friedbert Weiss, a professor of neuroscience at Scripps Research and an author of the study. “They are trying to unlearn powerful negative states, such as the stress and anxiety of withdrawal. This work shows us which brain systems are responsible for locking in this type of learning, and why it can make relapse so persistent.”

“This is a brain area that just lit up in every mouse that went through withdrawal-related learning,” says co-author Hermina Nedelescu of Scripps Research. “It shows us the circuits that are recruited when the brain associates alcohol with relief from stress—and that may be a change in how we think about relapse.”

From behavior to brain maps

An estimated 14.5 million people in the United States suffer from alcohol use disorder, which includes a range of unhealthy drinking behaviors. Like other drug addictions, alcoholism is characterized by cycles of withdrawal, abstinence, and relapse.

In 2022, Weiss and Nedelescu used mice to study the types of learning that occur in the brain during this cycle. When rats initially start drinking, they learn to associate pleasure with alcohol and to seek out more. However, this conditioning becomes much stronger during multiple cycles of withdrawal and relapse. After learning that alcohol alleviated unpleasant feelings of withdrawal — what scientists call negative reinforcement or alleviation of the “state of negativity” — the animals sought more alcohol and would remain persistent even when uncomfortable.

“When rats learn to associate environmental stimuli or contexts with the experience of relief, they end up with an incredibly strong desire to seek alcohol in the presence of those stimuli—even if conditions are presented that require significant effort to engage in alcohol seeking,” Weiss says. “That is, these mice seek alcohol even if the behavior is punished.”

In the new work, the team wanted to determine exactly what cell networks in the brain learn to associate environmental cues with alleviating this negative state.

The researchers used advanced imaging tools to scan the entire brains of mice, cell by cell, and identify areas that became more active in response to alcohol-related cues. They compared four groups of rats: those that had gone through withdrawal and learned that alcohol alleviated a negative state, and three different control groups that had not.

While several brain regions showed increased activity in mice that had learned withdrawal, one stood out: the PVT, known for its role in stress and anxiety.

“In retrospect, this makes a lot of sense,” Nedelescu says. “The unpleasant effects of alcohol withdrawal are strongly linked to stress, and alcohol provides relief from the suffering of that stressful state.”

Researchers hypothesize that this negative pleasure state, and the activation of the brain’s PVT as a response, is critical to how the brain learns and perpetuates addiction.

Better understanding of addiction

The implications of the new study go beyond alcohol, researchers say. Conditioned environmental stimuli of negative reinforcement—the drive to act in order to escape pain or stress—are a universal feature of the brain, and can drive human behavior beyond substance use disorders such as anxiety disorders, fear conditioning, and learning to avoid trauma.

“This work has potential applications not only for alcoholism, but also other disorders where people get trapped in harmful cycles,” Nedelescu says.

Future research will expand even further. Nedelescu and his colleagues at Scripps Research want to expand the study to females and examine the neurochemistry released in the PVT when people encounter environments associated with experiencing such relief from a negative state of mind. If they can identify the molecules involved, it could open new avenues for drug development by targeting those molecules.

Now, the new study underscores a major shift in how basic scientists think about addiction.

“As psychologists, we’ve known for a long time that addiction isn’t just about chasing pleasure—it’s about escaping those negative pleasure states,” Weiss says. “This study shows us where learning is rooted in the brain, and is a step forward.”

In addition to Weiss and Nedelescu, authors of the study, “Recruitment of neural populations in the hypothalamus of striatal seeking dogs with withdrawal-related learning experience,” are Elias Mamari, Nami Rajaei, Alexus Gray, Ryan Bullard, and Nobuyoshi Suto; and Nathan O’Connor of MBF Bioscience.

This work was supported by funding from the National Institutes of Health (Ruth L. Kirschstein National Service Award T32AA007456, K01 DA05449, R01 AA027555, and R01 AA023183).