Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects

Cocaine blocks the reuptake of dopamine, a neurotransmitter involved in the control of movement, cognition, motivation and reward. This leads to an increase in extracellular dopamine; the reinforcing effect of cocaine is associated with elevated dopamine levels in the nucleus accumbens1,2. But addiction to cocaine involves other effects, such as craving, loss of control and compulsive drug intake; the role of the dopamine system in these effects is less well-understood. We therefore used positron emission tomography (PET) to compare the responses of cocaine addicts and normal controls to intravenous methylphenidate, a drug that, like cocaine, causes an increase in synaptic dopamine3. Addicts showed reduced dopamine release in the striatum, the brain region where the nucleus accumbens is located, and also had a reduced 'high' relative to controls. In contrast, addicts showed an increased response to methylphenidate in the thalamus (a region that conveys sensory input to the cortex). This thalamic response was associated with cocaine craving and was not seen in control subjects. Thus, our findings challenge the notion that addiction involves an enhanced striatal dopamine response to cocaine and/or an enhanced induction of euphoria. Moreover, they suggest a participation of thalamic dopamine pathways in cocaine addiction, a possibility that merits further investigation.