title: Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818c/g polymorphism.
abstract: BACKGROUND
  The functional catechol-O-methyltransferase (COMT) valine158methionine (val158met) polymorphism determines prepulse inhibition (PPI) levels and working memory performance and the effects of tolcapone on these functions. Here, we explored the effects of the synonymous COMT rs4818 C/G polymorphism and tolcapone on PPI and working memory.
  
  
  METHODS
  Thirteen G/G (low prefrontal cortex [PFC] dopamine [DA]) and 12 C/C (high PFC DA) healthy male subjects entered and completed the study. Subjects participated in two weekly sessions associated with either acute oral tolcapone (200 mg) or placebo according to a balanced, crossover, double-blind design. Prepulse inhibition was assessed with 5 dB and 15 dB above background prepulses at 30-msec, 60-msec, and 120-msec intervals. Subjective mood and working memory performance (n-back and letter-number sequencing) were also assessed.
  
  
  RESULTS
  Prepulse inhibition was lower and reaction time in the n-back was slower in the G/G compared with the C/C group in the placebo condition. Tolcapone increased PPI and improved performance in both working memory tasks in the G/G group only. Baseline startle was greater in the C/C group and was not affected by tolcapone. Mood profile was worse in the C/C group and tended to deteriorate with tolcapone. Status of val158met alone could not explain these results.
  
  
  CONCLUSIONS
  Catechol-O-methyltransferase haplotype analyses are essential in future research. Prepulse inhibition and working memory may both relate to PFC DA levels according to an inverted U-shaped curve function. Tolcapone could be potentially useful in the treatment of conditions with deficient sensorimotor gating and working memory such as schizophrenia and prodromal states but only in a genotype-specific manner.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Crete, Greece. roussosp@edu.med.uoc.gr
authors.forename: Panos
authors.initials: P
authors.lastname: Roussos
authors.forename: Stella G
authors.initials: SG
authors.lastname: Giakoumaki
authors.forename: Panos
authors.initials: P
authors.lastname: Bitsios
mesh_terms: D000328:Adult; D000339:Affect / Q000187:drug effects*; D001577:Benzophenones / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects*; D009596:Nitrophenols / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D011597:Psychomotor Performance / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D055139:Sensory Gating / Q000187:drug effects* / Q000235:genetics; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase