Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction

Abstract

The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and [11C]raclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of [11C]raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [11C]raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.

Figure 1.

Brain maps obtained with SPM showing the difference in the distribution volume of [¹¹C]raclopride between the neutral and the cocaine-cue conditions (p < 0.05, uncorrected, threshold >100 voxels). Note that there were no differences in the ventral striatum (−8 canthomeatal plane).

Figure 2.

A, Dopamine D₂ receptor availability (Bmax/Kd) in caudate, putamen, and ventral striatum for the neutral and the cocaine-cue conditions. B, Craving measures (assessed with the CCQ) before (pre) and after (post) presentation of the neutral and the cocaine videos. C, Regression slopes for the correlation between changes in DA (percentage changes in Bmax/Kd from the neutral condition) and changes in cocaine craving (pre and post differences in CCQ scores). Values represent means ± SDs. Comparisons correspond to paired t tests (two-tailed) *p < 0.05; **p < 0.01.