Differential involvement of the prelimbic cortex and striatum in conditioned heroin and sucrose seeking following long-term extinction

Relapse to drug taking is triggered by stimuli previously associated with consumption of drugs of misuse (cues) and involves brain systems controlling motivated behaviour towards natural reinforcers. In this study, we aimed to identify and compare neuronal pathways in corticostriatal systems that control conditioned heroin or natural reward (sucrose) seeking. To that end, rats were trained to self-administer heroin or sucrose in association with an identical compound cue. After more than 3 weeks of abstinence during extinction training, cue exposure robustly reinstated heroin and sucrose seeking, but induced distinct and even opposing changes in the expression of the neuronal activation marker zif268 in the prelimbic cortex and striatal complex, respectively. Because in the prelimbic area zif268 expression was enhanced during cue-induced heroin seeking but unaffected during sucrose seeking, a pharmacological intervention was aimed at this prefrontal region. Injection of a GABA agonist mixture within the prelimbic area enhanced conditioned heroin seeking, but had no effect on conditioned sucrose seeking. Our findings suggest a differential role of the prelimbic area and the striatum in the persistence of heroin vs. sucrose seeking following long-term extinction.