'Anti-reward' brain network helps explain cocaine addiction

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. Now researchers at The Hebrew University of Jerusalem have revealed that it’s not just the craving for pleasure that plays a powerful role in relapse — it’s also the brain’s aversion to pain.

Led by Professor Yonatan M Kupchik and PhD student Liran Levi, and published in the journal Science Advances, the new 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.

While the ventral pallidum is known for regulating pleasure and reward, the team’s 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,” Kupchik said. “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 centres 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.

In a surprising 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.

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.

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