Elsevier

NeuroImage

Volume 39, Issue 3, 1 February 2008, Pages 1266-1273
NeuroImage

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

https://doi.org/10.1016/j.neuroimage.2007.09.059Get rights and content

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 [11C]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.

Section snippets

Subjects

Twenty active cocaine-addicted subjects who responded to an advertisement were studied. Subjects fulfilled DSM-IV criteria for cocaine dependence and were active users for at least the prior 6 months (free-base or crack, at least “4 g” a week). Exclusion criteria included current or past psychiatric disease other than cocaine dependence; past or present history of neurological, cardiovascular or endocrinological disease; history of head trauma with loss of consciousness greater than 30 min; and

Concentration of MP in plasma

The plasma levels of MP did not differ between the two conditions of administration. These levels corresponded for the cocaine cue and the neutral video conditions respectively to 3 ± 1 and 4 ± 3 ng/ml at 30 min; to 7 ± 3 and 7 ± 4 ng/ml at 60 min; to 7 ± 2 and 8 ± 3 ng/ml at 90 min; and to 5 ± 2 and 6 ± 2 ng/ml at 120 min after its administration. The correlation between plasma MP concentration and the cardiovascular, behavioral and DA measures were not significant.

Effects of MP on the cardiovascular measures when exposed to the cocaine video versus the neutral video

The changes in cardiovascular measures (pre  

DA and craving

Here we show that MP significantly increased extracellular DA in striatum but that it induced craving only when administered with the cocaine cue video. Moreover the craving measures were only elevated after the subjects had been exposed to the cocaine cue video but not prior to it. Though prior studies in cocaine abusers had shown that cue-induced DA increases in striatum were associated with craving (Volkow et al., 2006, Wong et al., 2006), the current findings indicate that striatal DA

Conclusion

Here we show that slow increases in DA as achieved with oral MP were not associated with craving when there was no concomitant presentation of conditioned cues. This suggests that DA increases associated with conditioned cues reflect secondary responses to activation of pathway(s) that modulate DA cell firing and release (i.e., fronto-striatal and fronto-mesencephalic glutamatergic pathways). Moreover fast DA changes as triggered by phasic DA cell firing may underlie craving rather than the

Acknowledgments

We thank David Alexoff, Pauline Carter, Barbara Hubbard, Lisa Muench, Kith Pradhan, Colleen Shea, David Schlyer, Michael Schueller, Paul Vaska, Don Warner, Youwen Xu, Karen Apelskog and Linda Thomas for their contributions. Research supported by NIH’s Intramural Research Program (NIAAA), NIDA (DA06278-15), GCRC (MO1RR10710) and by DOE (DE-AC01-76CH00016) and for Dr. Childress (VA VISN 4 MIRECC and the DANA Foundation).

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