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.