Study shows lasting stress-related brain changes increase alcohol relapse risk.
Alcohol use disorder remains one of the most difficult conditions to treat, in large part because many people return to drinking even after long periods without alcohol. New research from Scripps Research Institute offers a clearer picture of why stress plays such a powerful role in relapse. The findings point to changes deep in the brain that continue long after drinking has stopped, helping explain why staying sober can feel like a constant struggle.
Alcohol use disorder is defined by the inability to control drinking despite clear harm. In the United States, close to 28 million people live with this condition. While some medications are approved to reduce cravings, their benefits are limited, and side effects often cause people to stop taking them. For many, stress remains one of the strongest triggers for relapse, even months or years into recovery.
The new study focused on how long-term alcohol use alters stress-related brain signaling. Drinking does not only affect mood and behavior; it also activates the body’s stress systems. Over time, this repeated activation appears to rewire how certain brain circuits respond. Once these systems are altered, stress may more easily push someone back toward alcohol.
Researchers examined two chemical messengers in the brain called orexin and dynorphin. These messengers are released by the same nerve cells and normally work in balance. Orexin acts like a green light, encouraging action and reward-seeking. Dynorphin works like a brake, limiting reward and producing discomfort that helps stop harmful behavior. In a healthy brain, the push and pull between these signals helps regulate motivation.
Heavy drinking disrupts this balance. Earlier work showed that dynorphin becomes linked to the unpleasant feelings of withdrawal, such as anxiety and irritability. These feelings can drive people to drink again to find relief. In the new study, scientists looked closely at a small brain region involved in stress responses called the posterior paraventricular nucleus of the thalamus. This area helps connect stress to motivated behavior and has been tied to relapse.
Using a rat model of alcohol dependence, researchers found lasting changes in how orexin and dynorphin systems function. After alcohol was removed, the part of the brain that produces these signals increased output of both messengers. At the same time, the stress-processing region showed fewer receptors for orexin and more receptors for dynorphin. This shift suggests that the brain becomes more sensitive to stress-related discomfort while losing some control over motivation.
These changes did not disappear with abstinence. Even after alcohol was no longer available, the altered signaling remained. This finding supports the idea that alcohol dependence leaves a long-term imprint on the brain, making relapse more likely when stress appears.
The study also tested what happens when these signals are blocked. When orexin signaling was reduced, stressed animals were less likely to seek alcohol. This result matched expectations. Surprisingly, blocking dynorphin also lowered alcohol-seeking behavior. When both signals were blocked at the same time, however, the protective effects disappeared. The animals behaved as if no treatment had been given.
Because the research focused on one brain region and only male animals, the results cannot yet be directly applied to people. Still, the findings raise important warnings for drug development. Combining treatments that target stress and motivation may have unexpected effects if the balance between brain signals is disrupted.
Researchers are now exploring more precise drugs that act quickly and wear off fast, which may help reduce side effects. There is also interest in pairing these drugs with existing sleep medications that affect orexin. Together, these approaches may one day lead to safer options for reducing relapse risk.
The study adds to growing evidence that alcohol use disorder is not simply a matter of choice or willpower. Lasting brain changes tied to stress help explain why recovery is often uneven and why support over time remains essential.
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Altered stress signaling helps explain relapse in alcohol use disorder
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