title: Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers.
abstract: BACKGROUND
  Attention is the capacity to flexibly orient behaviors and thoughts towards a goal by selecting and integrating relevant contextual information. The dorsal cingulate (dCC) and prefrontal (PFC) cortices play critical roles in attention. Evidence indicates that catechol-O-methyltransferase (COMT) modulates dopaminergic tone in the PFC and dCC.
  
  
  OBJECTIVE
  In this study, we explored the effect of tolcapone, a CNS penetrant COMT inhibitor that increases cortical dopamine levels, on brain activity during a Variable Attentional Control (VAC) task.
  
  
  METHODS
  We performed a double-blinded, placebo-controlled, counter-balanced trial with tolcapone (Tasmar, tablets, 100 mg three times a day for 1 day and then 200 mg three times a day for 6 days; ClinicalTrials.gov identifier: NCT00044083).
  
  
  METHODS
  The study was conducted in the Clinical Center of the National Institute of Mental Health from 2005 to 2009.
  
  
  METHODS
  Twenty healthy volunteers (11 males; mean age = 32.7 years) with good imaging and performance data on both arms of the study were investigated.
  
  
  METHODS
  Participants underwent 3T blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) while performing the event-related VAC task, which varies attention over three levels of load: LOW, INT (intermediate), and HIGH.
  
  
  METHODS
  Changes in behavioral data and individual contrast images were analyzed using ANOVA with drug and task load as co-factors.
  
  
  RESULTS
  There was a significant main effect of increasing task load, with resulting decreased accuracy and increased reaction time. While there was no significant effect of tolcapone on these behavioral measures, the neuroimaging data showed a significant effect on load-related changes in dCC, with significantly lower dCC activation on tolcapone compared with placebo. Further, neural activity in dCC correlated positively with COMT enzyme activity (i.e., lower COMT activity and presumably more dopamine was associated with lower activation in dCC, i.e., more efficient information processing).
  
  
  CONCLUSIONS
  Our results show that pharmacological reduction of COMT activity modulates the engagement of attentional mechanisms, selectively enhancing the efficiency of dCC processing in healthy volunteers, reflected as decreased activity for the same level of performance.
authors.affiliation: Clinical Brain Disorders Branch (CBDB), National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: Sophia C
authors.initials: SC
authors.lastname: Magalona
authors.forename: Roberta
authors.initials: R
authors.lastname: Rasetti
authors.forename: Jingshan
authors.initials: J
authors.lastname: Chen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Ian
authors.initials: I
authors.lastname: Gold
authors.forename: Heather
authors.initials: H
authors.lastname: Decot
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Karen F
authors.initials: KF
authors.lastname: Berman
authors.forename: José A
authors.initials: JA
authors.lastname: Apud
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001288:Attention / Q000187:drug effects; D001577:Benzophenones / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D065098:Catechol O-Methyltransferase Inhibitors; D018592:Cross-Over Studies; D004298:Dopamine / Q000378:metabolism; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D011597:Psychomotor Performance / Q000187:drug effects*; D000077867:Tolcapone; D055815:Young Adult
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone; D010100:Oxygen; D004298:Dopamine