title: Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.
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.
authors.affiliation: National Institute on Drug Abuse, Bethesda, Maryland, United States of America. nvolkow@nida.nih.gov
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.forename: Gene-Jack
authors.initials: GJ
authors.lastname: Wang
authors.forename: Dardo
authors.initials: D
authors.lastname: Tomasi
authors.forename: Frank
authors.initials: F
authors.lastname: Telang
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.forename: Kith
authors.initials: K
authors.lastname: Pradhan
authors.forename: Millard
authors.initials: M
authors.lastname: Jayne
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.forename: Rita Z
authors.initials: RZ
authors.lastname: Goldstein
authors.forename: Nelly
authors.initials: N
authors.lastname: Alia-Klein
authors.forename: Christopher
authors.initials: C
authors.lastname: Wong
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D003042:Cocaine / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos; D049268:Positron-Emission Tomography
chemical_list: D018765:Dopamine Uptake Inhibitors; D010919:Placebos; D019788:Fluorodeoxyglucose F18; D008774:Methylphenidate; D003042:Cocaine; D004298:Dopamine