Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement.

The value of rewards (natural rewards and drugs) is associated with dopamine increases in the nucleus accumbens and varies as a function of context. The prefrontal cortex has been implicated in the context dependency of rewards and in the fixated high value that drugs have in addiction, although the mechanisms are not properly understood. Here we test the hypothesis that the prefrontal cortex regulates the value of rewards by modulating dopamine increases in nucleus accumbens and that this regulation is disrupted in addicted subjects. We used positron emission tomography to evaluate the activity of the prefrontal cortex (measuring brain glucose metabolism with [18F]fluorodeoxyglucose) and dopamine increases (measured with [11C]raclopride, a D2/D3 receptor ligand with binding that is sensitive to endogenous dopamine) induced by the stimulant drug methylphenidate in 20 controls and 20 detoxified alcoholics, most of whom smoked. In all subjects, methylphenidate significantly increased dopamine in striatum. In ventral striatum (where the nucleus accumbens is located) and in putamen, dopamine increases were associated with the rewarding effects of methylphenidate (drug liking and high) and were profoundly attenuated in alcoholics (70 and 50% lower than controls, respectively). In controls, but not in alcoholics, metabolism in orbitofrontal cortex (region involved with salience attribution) was negatively associated with methylphenidate-induced dopamine increases in ventral striatum. These results are consistent with the hypothesis that the orbitofrontal cortex modulates the value of rewards by regulating the magnitude of dopamine increases in the ventral striatum and that disruption of this regulation may underlie the decreased sensitivity to rewards in addicted subjects.