A large-scale c-Fos brain mapping study on extinction of cocaine-primed reinstatement

Individuals with cocaine addiction can experience many craving episodes and subsequent relapses, which represents the main obstacle to recovery. Craving is often favored when abstinent individuals ingest a small dose of cocaine, encounter cues associated with drug use or are exposed to stressors. Using a cocaine-primed reinstatement model in rat, we recently showed that cocaine-conditioned interoceptive cues can be extinguished with repeated cocaine priming in the absence of drug reinforcement, a phenomenon we called extinction of cocaine priming. Here, we applied a large-scale c-Fos brain mapping approach following extinction of cocaine priming in male rats to identify brain regions implicated in processing the conditioned interoceptive stimuli of cocaine priming. We found that cocaine-primed reinstatement is associated with increased c-Fos expression in key brain regions (e.g., dorsal and ventral striatum, several prefrontal areas and insular cortex), while its extinction mostly disengages them. Moreover, while reinstatement behavior was correlated with insular and accumbal activation, extinction of cocaine priming implicated parts of the ventral pallidum, the mediodorsal thalamus and the median raphe. These brain patterns of activation and inhibition suggest that after repeated priming, interoceptive signals lose their conditioned discriminative properties and that action-outcome associations systems are mobilized in search for new contingencies, a brain state that may predispose to rapid relapse.