Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking.

Relapse represents a significant barrier to the successful treatment of cocaine addiction. Here, we characterize the relative activation of glutamatergic inputs to nucleus accumbens during cued reinstatement of cocaine seeking versus sucrose seeking. Prelimbic cortex (PL) projections to nucleus accumbens core (NAcC) uniquely expressed Fos in a manner that positively correlated with cocaine-seeking, but not sucrose-seeking, behavior. Additional functional experiments showed that the PL-NAcC pathway was recruited by drug-associated cues in a dopamine-dependent manner to drive cocaine-seeking, but not sucrose-seeking, behavior. These data highlight PL neurons that project to NAcC, and their regulation by dopamine, as potential targets for therapeutics designed to treat cocaine relapse that do not affect natural reward seeking.