Jerusalem, 23 July, 2025 (TPS-IL) — A new Israeli study released on Wednesday challenges long-held assumptions about drug addiction and opens new avenues for Treatment.
Published in the peer-reviewed Science Advances, the research by scientists from Hebrew University of Jerusalem identifies a previously unrecognized brain circuit that becomes hyperactive during cocaine withdrawal. This “anti-reward” network, located in the ventral pallidum, appears to amplify emotional distress and push individuals back toward drug use — not for the high, but to escape the low.
Led by Prof. Yonatan M. Kupchik and PhD student Liran A. Levi at the Faculty of Medicine, the study is among the first to show that a specific population of glutamatergic neurons in the ventral pallidum — traditionally associated with reward — actually suppress dopamine activity and trigger negative emotional states during abstinence.
“This is a network that turns up the volume on emotional suffering,” said Prof. Kupchik. “It doesn’t just track pleasure — it encodes the pain of not using, and that pain can be a powerful force driving relapse.”
The researchers found that this anti-reward circuit becomes more active during withdrawal and more connected to other emotional centers in the brain, increasing the user’s sensitivity to Stress and discomfort. Strikingly, when cocaine is reintroduced, the circuit rapidly quiets — creating a stark contrast that reinforces the cycle of relief-seeking.
But the most unexpected discovery came when researchers experimentally inhibited this circuit. Instead of reducing drug-seeking behavior, the suppression actually increased motivation to use cocaine.
“This suggests that the discomfort created by the anti-reward network may serve a protective purpose,” said Kupchik. “It’s the brain’s way of signaling danger — essentially creating an emotional cost to drug use.”
The findings mark a significant shift in how scientists understand addiction. Rather than focusing solely on the pursuit of pleasure, the study reframes relapse as a response to unresolved emotional pain—and identifies a concrete neural mechanism behind it.
While most current therapies aim to dampen the brain’s reward pathways, this study suggests that targeting the emotional pain circuits of withdrawal could offer a more effective route to Treatment.
Future drug development could focus on modulating this circuit — not to shut it down completely, but rather to fine-tune its activity to reduce excessive emotional suffering while preserving its protective role.
Because many current behavioral interventions are based on the assumption that pleasure-seeking drives relapse, new therapies could shift to directly addressing withdrawal-related distress, such as anxiety, dysphoria, or emotional hypersensitivity. Cognitive-behavioral therapy (CBT) protocols could be adapted to help individuals better tolerate or reframe negative emotional states during abstinence.
Moreover, if the ventral pallidum circuit proves to be measurable via imaging or other bio-signals in humans, it could be used as a biomarker to identify individuals at high risk of relapse, track treatment response and personalize addiction therapy based on neural activity profiles.
Although the study focused on cocaine, the identified anti-reward mechanism may be relevant to other substance use disorders involving intense withdrawal symptoms, such as alcohol or opioids.
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