Anti-reward brain circuit may hold key to treating cocaine addiction

Why do so many people relapse after quitting cocaine? A new study from The Hebrew University reveals that a specific "anti-reward" brain circuit becomes hyperactive during withdrawal-driving discomfort and pushing users back toward the drug. Surprisingly, this circuit may also serve as a built-in protective mechanism, offering new hope for addiction treatment.

Cocaine addiction has long been understood as a tug-of-war between reward and restraint. The rush of dopamine keeps users hooked, while withdrawal triggers anxiety, depression, and despair. But a new study by researchers at The Hebrew University of Jerusalem reveals that it's not just the craving for pleasure-but the brain's aversion to pain-that plays a powerful role in relapse.

Led by Prof. Yonatan M. Kupchik and PhD student Liran Levi from the Faculty of Medicine, the study identifies a specific "anti-reward" network deep in the brain that undergoes lasting changes during cocaine use, withdrawal, and re-exposure. This glutamatergic network, located in the ventral pallidum, is emerging as a key player in addiction-and a promising target for future therapies.

The rollercoaster inside the brain

While the ventral pallidum is known for regulating pleasure and reward, this research highlights a lesser-known group of neurons that suppress dopamine release and amplify negative emotions. During abstinence, this anti-reward network ramps up its activity-intensifying discomfort and emotional distress. When cocaine is reintroduced, the network quickly quiets, reinforcing the cycle of relief-seeking and relapse.

"It's a switch," says Prof. Kupchik. "This network tracks the emotional cost of abstinence. When it's highly active, it can drive someone to seek out the drug again-just to escape the negative feelings."

The study also shows that this brain circuit connects with other key centers involved in emotional regulation and reward processing. During withdrawal, these connections become stronger, increasing sensitivity to negative emotional states. When the drug returns, the system resets-temporarily easing distress.

Surprisingly, discomfort may serve a purpose

In a striking finding, the researchers discovered that when this anti-reward circuit was inhibited, drug preference and motivation actually increased. This suggests that the brain's negative signals may serve a protective role-creating an internal brake that discourages excessive drug use by making it emotionally costly.

A shift in the addiction treatment paradigm

While most current addiction therapies aim to dampen the brain's reward system, this study points to a different path: targeting the emotional pain of withdrawal. By understanding and potentially modulating the brain's aversive signals, future treatments may better address the root causes of relapse.

Published by PhD student Liran A. Levi and Prof. Kupchik at Hebrew University's IMRIC Center for Addiction Research (ICARe), the study offers a new framework for understanding addiction-not just as the pursuit of pleasure, but as the escape from pain.