Drug-related cues are potent triggers for relapse in people with cocaine dependence. Dopamine (DA) release within a limbic network of striatum, amygdala and hippocampus has been implicated in animal studies, but in humans it has only been possible to measure effects in the striatum. The objective here was to measure drug cue-induced DA release in the amygdala and hippocampus using high-resolution PET with [ 18 F]fallypride. Twelve cocaine-dependent volunteers (mean age: 39.6 ± 8.0 years; years of cocaine use: 15.9 ± 7.4) underwent two [ 18 F]fallypride high-resolution research tomography-PET scans, one with exposure to neutral cues and one with cocaine cues. To our knowledge this study provides the first evidence of drug cue-induced DA release in the amygdala and hippocampus in humans. The preferential induction of DA release among high-craving responders suggests that these aspects of the limbic reward network might contribute to drug-seeking behavior.

IntroductionThe prefrontal cortex (PFC) integrates and interprets sensory information, processing value, directing attention, and planning actions based on experience.1,2 In cocaine-dependent individuals, these regions and processes are engaged by drug-related cues, increasing the likelihood of craving and drug pursuit.3-5 For each of these effects, dopamine (DA) is a plausible contributing transmitter. Mesocortical DA transmission plays a critical role in cognitive and executive functions, 6 and, in laboratory animals, DA infusions into the PFC reinstate cocaine-seeking behaviours 7,8 while DA depletion or receptor antagonists reduce the drug's reinforcing efficacy. 9Based on these observations, it has been proposed that PFC abnormalities seen in cocaine-dependent individuals 10 are related at least in part to experience-dependent changes in DA transmission. 11,12 Dopamine release in the human PFC and striatum can be measured following an amphetamine challenge with positron emission tomography (PET) and the 18 F-labelled tracer fallypride. 13,14 More recently, the radioligand's PFC sensitivity to nonpharmacological manipulations of the DA system has also been demonstrated using psychological stressors.15-17 Here, we used [ 18 F]fallypride and high-resolution PET to assess the ability of drug-related cues to elicit DA release in the PFC of volunteers meeting criteria for current cocaine dependence. Given the role of DA in conditioned approach and incentive learning, 18 we hypothesized that exposure to familiar, drugrelated stimuli would enhance DA signalling in prefrontal and, in particular, orbitofrontal regions, contributing to the generation of motivational states that lead to drug seeking. 5,19Based on earlier reports identifying an association between PFC activation and self-reported craving, 3,20,21 a positive correlation between PFC DA release and craving was predicted. , 2015; Revised Sept. 9, 2015; Accepted Oct. 19, 2015; Early-released Feb. 23, 2016 DOI: 10.1503 Background: Accumulating evidence indicates that drug-related cues can induce dopamine (DA) release in the striatum of substance abusers. Whether these same cues provoke DA release in the human prefrontal cortex remains unknown. Methods: We used highresolution positron emission tomography with [