Drugs of abuse are rewarding to addicted and nonaddicted subjects, but they trigger craving and compulsive intake only in addicted subjects. Here, we used positron emission tomography (PET) and [18F] deoxyglucose to compare the brain metabolic responses (marker of brain function) of cocaine-addicted subjects (n = 21) and controls (n = 15) to identify brain regions that are uniquely activated in addicted subjects by intravenous methylphenidate (a drug that cocaine-addicted subjects report to be similar to cocaine). In parallel, we also measured the changes in dopamine (DA) induced by intravenous methylphenidate (using PET and [11C] raclopride) in the striatum and in the thalamus. Metabolic responses between groups differed significantly only in the right medial orbital prefrontal cortex [Brodmann's area (BA) 25 and medial BA 11], where methylphenidate increased metabolism in addicted subjects but decreased metabolism in controls. These changes were associated in all subjects with increased "desire for methylphenidate" and in the addicted subjects with "cocaine craving." In addicted subjects, increases in BA 25 were also associated with mood elevation. Methylphenidate-induced increases in metabolism in the medial orbital prefrontal cortex were associated with its increase of DA in the thalamus but not in the striatum. These findings provide evidence that enhanced sensitivity of BA 25 (region involved with emotional reactivity) and BA 11 (region involved with salience attribution and motivation) in cocaine-addicted subjects may underlie the strong emotional response to the drug and the intense desire to procure it that results in craving and compulsive drug intake. It also suggests that the mesothalamic DA pathway may contribute to these processes.
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