Dopamine increases in striatum do not elicit craving in cocaine abusers unless they are coupled with cocaine cues

Abstract

Imaging studies have shown an association between dopamine increases in striatum and cue induced craving in cocaine abusers. However, the extent to which dopamine increases reflect a primary rather than a secondary response to the cues remains unclear. Here we evaluated the extent to which dopamine increases by themselves can induce craving in cocaine abusers. Using PET and [(11)C]raclopride (D2 receptor radioligand sensitive to competition with endogenous dopamine) we show that in cocaine abusers (n=20) oral methylphenidate (20 mg), which significantly increased dopamine in striatum, did not induce craving unless subjects were concomitantly exposed to cocaine cues (video scenes of subjects self-administering cocaine). This suggests that dopamine increases associated with conditioned cues are not primary responses but reflect downstream stimulation of dopamine cells (presumably glutamatergic afferents from prefrontal cortex and/or amygdala). Inasmuch as afferent stimulation of dopamine neurons results in phasic cell firing these findings suggest that "fast" dopamine increases, in contrast to the "slow" dopamine increases as achieved when using oral methylphenidate (mimicking tonic dopamine cell firing), are required for cues to trigger craving. The fact that methylphenidate induced craving only when given with the cocaine cues highlights the context dependency of methylphenidate's effects and suggests that its use for the treatment of ADHD subjects with co-morbid drug abuse should not increase craving.

Figure 1

Cardiovascular measures for the placebo neutral-cue, the MP neutral-cue and the MP cocaine-cue conditions. Significant increases in heart rate and systolic blood pressure were observed only for the MP cocaine-cue condition. Values correspond to means and standard deviations.

Figure 2

Average values on the Cocaine Craving Scale for the 3 conditions, before administration of the drug or placebo (Pre-drug/Pre-video), 55 minutes after administration of the drug but prior to video (Post-drug/Pre-video) and at the end of the video (Post-drug/Post-video). MP significantly increased craving only after watching the cocaine video. * Repeated ANOVA (F = 16.4, p < 0.0001); Post-hoc t tests for post-MP/post-video versus pre-MP/pre-video (p < 0.0005) and for post-MP/post-video versus post-MP/pre-video (p < 0.0005). Values correspond to means and standard deviations.

Figure 3

SPM results for the areas where the distribution volume ratio (DVR) for [¹¹C]raclopride was significantly decreased by methylphenidate both when given with the cocaine-cue video and when given with the neutral-cue video as compared to the placebo neutral-cue video condition (p < 0.01, uncorrected 100 pixels). Methylphenidate decreased [¹¹C]raclopride’s specific binding in dorsal striatum for both conditions but decreased it in the ventral striatum only when given with the neutral-cue video.

Figure 4

SPM results for the areas where the changes in the distribution volume ratio (DVR) differed when MP was given with the neutral-cue than with the cocaine-cue video. Changes were greater in ventral striatum when MP was given with the neutral than the cocaine-cue video (p < 0.05, uncorrected).