A ventral pallidal glutamatergic aversive network encodes abstinence from and reexposure to cocaine.

Relapse to drugs of abuse can occur after long periods of abstinence. The ventral pallidum (VP) is central to drug addiction, and its glutamatergic neurons (VPGlu), whose activation drives aversion, inhibit drug seeking. However, it remains unknown whether these neurons encode the abstinence from and relapse to drugs. We show here that VPGlu projections specifically to the aversion-related lateral habenula (LHb) and ventral tegmental area gabaergic (VTAGABA) neurons show plasticity induced by abstinence from and reexposure to cocaine or cocaine cues. Both these pathways potentiate during abstinence and restore baseline values upon drug reexposure but with different plasticity mechanisms. Last, inhibiting the VPGlu → LHb pathway enhances cocaine preference after abstinence, while inhibiting the VPGlu → VTA pathway shows variable effects. These findings establish an aversive circuit orchestrated by VPGlu neurons encoding long-term abstinence-driven changes that may contribute to drug relapse.