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Randomized Controlled Trial
. 2010 Jul 9;5(7):e11509.
doi: 10.1371/journal.pone.0011509.

Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers

Nora D Volkow  1 , Gene-Jack Wang, Dardo Tomasi, Frank Telang, Joanna S Fowler, Kith Pradhan, Millard Jayne, Jean Logan, Rita Z Goldstein, Nelly Alia-Klein, Christopher Wong
Affiliations
Randomized Controlled Trial

Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers

Nora D Volkow et al. PLoS One. .

Abstract

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and (18)FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. SPM results on the Video comparison (Neutral vs Cocaine-cues video) for the Placebo (PL), for the Methylphenidate (MP) and for both conditions (PL and MP) done on normalized metabolic images (Cocaine-Cues < Neutral).
The Cocaine-cues lowered glucose metabolism and this effect was attenuated when subjects were given MP. Threshold of significance p<0.005 uncorrected, cluster size >200 voxels.
Figure 2
Figure 2. SPM results on the Drug comparison (Placebo vs MP) for the Neutral Video, for the Cocaine-Cues Video and for both conditions (Neutral and Cocaine-Cues) done on normalized metabolic images (MP < PL).
MP decreased metabolism in superior parietal regions. Threshold of significance p<0.01 uncorrected, cluster size >200 voxels.
Figure 3
Figure 3. SPM results for the Video (Neutral vs Cocaine-cues) by Drug (Placebo vs MP) interaction (MP < PL).
Methylphenidate resulted in less metabolic changes than the Placebo and there were no regions were the differences were greater for Methylphenidate than for the Placebo conditions. Threshold of significance p<0.01 uncorrected, cluster size >200 voxels.
Figure 4
Figure 4. SPM results for the voxel-wise correlation between changes in metabolism and changes in self-reports of cocaine craving (Neutral - Cocaine-cues) for the Placebo and the Methylphenidate conditions (p<0.005 uncorrected, cluster size >200 voxels).
For Placebo the correlations were negative (decreases in metabolism associated with increases in craving) whereas with Methylphenidate these were positive (increases in metabolism associated with increases in craving).
Figure 5
Figure 5. SPM results on comparison (Neutral vs Cocaine-cues video) for the Placebo (PL) and the Methylphenidate (MP) conditions done on normalized metabolic images for the Females (n = 8) and the Male subjects (n = 16).
The threshold of significance was set at p<0.005 uncorrected, cluster size >200 voxels. Females showed greater decreases to the Cocaine-cues when compared to the Neutral video than males.
Figure 6
Figure 6. Diagram of experimental protocol.
See this image and copyright information in PMC

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