Neural Correlates of the Formation and Retention of Cocaine-Induced Stimulus-Reward Associations

Background: Cocaine can elicit drug-seeking behavior for drug-predicting stimuli, even after a single stimulus-cocaine pairing. Although orbitofrontal cortex is thought to be important during encoding and maintenance of stimulus-reward value, we still lack a comprehensive model of the neural circuitry underlying this cognitive process. Methods: We studied the conditioned effects of cocaine with monkey functional magnetic resonance imaging and classical conditioning by pairing a visual shape (conditioning stimulus [CS+]) with a noncontingent cocaine infusion; a control stimulus was never paired. We correlated the behavioral preference of the monkey for the CS+, as measured offline, with the activity induced by the CS+ relative to the control stimulus as function of time. Results: We observed that during formation of stimulus-cocaine associations strong CS+-induced functional magnetic resonance imaging activations emerged in frontal cortex that correlated significantly with behavioral CS+ preference. Afterward, CS+ preference correlated only with activity in early visual cortex. Control experiments suggest that these findings cannot be explained by increased familiarity for the CS+. Conclusions: Our findings suggest a complex interaction between frontal and occipital cortex during cocaine conditioning. Frontal cortex is important for establishing novel representations of stimulus valence when cocaine is used as reinforcer, whereas early visual cortex is involved in retaining these cocaine-stimulus associations.