Summary: A new study from the Hebrew University of Jerusalem identifies a brain circuit that intensifies negative emotions during cocaine withdrawal and shows how that circuit can drive relapse. Researchers found that an “anti-reward” glutamatergic network in the ventral pallidum becomes more active during abstinence, heightening distress and motivating renewed drug use. At the same time, this same circuit appears to act as an internal brake, making drug-taking emotionally costly and possibly limiting excessive use.
These findings expand how we understand addiction: not only as a search for pleasure but also as an escape from aversive states. Targeting withdrawal-related emotional pain, rather than focusing solely on craving, may open new avenues for preventing relapse.
Key facts
- Anti-reward circuit: A ventral pallidal glutamatergic network amplifies negative emotion during cocaine abstinence.
- Relapse trigger: Heightened aversive feelings during withdrawal can push individuals back to cocaine to relieve distress.
- Protective role: In some conditions, the same aversive signaling reduces drug preference, acting like an internal brake.
Source: Hebrew University of Jerusalem
Why relapse often follows quitting cocaine
Cocaine addiction involves competing neural forces: reward circuits driven by dopamine that reinforce drug-taking, and other systems that limit consumption. Withdrawal commonly produces anxiety, low mood, and intense discomfort. The Hebrew University study shows that an aversive, glutamatergic circuit in the ventral pallidum becomes persistently altered by cocaine exposure and abstinence, amplifying the negative side of this tug-of-war and promoting relapse.
The research team, led by Prof. Yonatan M. Kupchik with PhD student Liran Levi at the Hebrew University Faculty of Medicine, focused on glutamatergic neurons in the ventral pallidum (VP). These neurons—referred to as VPGlu—are capable of suppressing dopamine-related reward signals and driving aversion. Using a combination of behavioral experiments and circuit-level measurements, the investigators tracked how VPGlu pathways change during drug use, during abstinence, and when the drug is reintroduced.
How the anti-reward circuit works
Within the ventral pallidum, VPGlu neurons project to regions involved in aversion and reward regulation, including the lateral habenula (LHb) and GABAergic neurons in the ventral tegmental area (VTAGABA). The study found that projections from VPGlu to these targets strengthen during abstinence—a change described as potentiation—making the brain more sensitive to negative states. When cocaine or cocaine-related cues are reintroduced, the potentiation subsides and activity returns toward baseline, producing a rapid reduction in aversive signaling that can reinforce renewed drug use.
Prof. Kupchik describes the circuit as a switch that signals the emotional cost of abstinence: when the circuit is highly active, the resulting distress can become a powerful driver of relapse because taking the drug brings temporary relief.
Aversive signaling can be protective
Counterintuitively, the team observed that experimentally inhibiting the VPGlu → LHb pathway increased cocaine preference after a period of abstinence. In other words, reducing aversive signaling made the drug more attractive, suggesting that the anti-reward system normally restrains excessive consumption by imposing an emotional penalty on continued use. Effects of inhibiting the VPGlu → VTA pathway were more variable, signaling that different downstream targets contribute in distinct ways.
Implications for addiction treatment
Most current interventions focus on dampening reward-driven craving or blocking the reinforcing effects of drugs. This study points to an alternative or complementary strategy: addressing the aversive states produced by withdrawal. By better understanding the neural circuits that encode abstinence-driven distress, researchers may develop therapies that reduce the emotional cost of quitting without removing the protective brake that helps limit excessive intake.
Published by Liran A. Levi and Prof. Yonatan M. Kupchik at the Hebrew University’s IMRIC Center for Addiction Research (ICARe), the work reframes relapse as a process shaped both by the pursuit of pleasure and the avoidance of pain. That dual perspective can help guide future research and clinical approaches targeting the neural roots of relapse.
About this addiction and mental health research news
Author: Danae Marx, Hebrew University of Jerusalem
Source: Hebrew University of Jerusalem
Contact: Danae Marx, Hebrew University of Jerusalem
Image credit: Neuroscience News
Original research: Open access. “A ventral pallidal glutamatergic aversive network encodes abstinence from and re-exposure to cocaine” by Liran A. Levi et al., published in Science Advances (DOI: 10.1126/sciadv.adu6074).
Abstract (concise)
Relapse after long periods of abstinence remains a major challenge in addiction. The ventral pallidum (VP) plays a central role, and its glutamatergic neurons (VPGlu) drive aversion and can suppress drug-seeking. This study demonstrates that VPGlu projections to the lateral habenula (LHb) and VTA GABAergic neurons show abstinence-induced potentiation that returns toward baseline upon drug reexposure. Inhibiting the VPGlu → LHb pathway increases cocaine preference after abstinence, indicating that this aversive circuit encodes long-term abstinence-driven changes that may contribute to relapse.