Improvement of prepulse inhibition and executive function by the COMT inhibitor tolcapone depends on COMT Val158Met polymorphism

Neuropsychopharmacology. 2008 Dec;33(13):3058-68. doi: 10.1038/npp.2008.82. Epub 2008 Jun 4.


Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and working memory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the COMT Val158Met polymorphism. Twelve Val/Val and eleven Met/Met healthy male subjects entered the study. Tolcapone 200 mg was administered in two weekly sessions, according to a balanced, crossover, double-blind, placebo-controlled design. PPI was assessed with 5 dB and 15 dB above background prepulses, at 30-, 60-, and 120 ms prepulse-pulse intervals. Subjects also underwent the n-back and the letter-number sequencing (LNS) tasks. PPI was lower in the Val/Val compared to the Met/Met group in the placebo condition. Tolcapone increased PPI significantly in the Val/Val group and tended to have the opposite effect in the Met/Met group. Baseline startle was not affected by tolcapone in the Val/Val group but it was slightly increased in the Met/Met group. Tolcapone improved performance in the n-back and LNS tasks only in the Val/Val group. Enhancement of PFC DA signaling with tolcapone improves both PPI and working memory in a COMT Val158Met genotype-specific manner. These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels according to an inverted U-shaped curve function.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Adult
  • Amino Acid Substitution / genetics
  • Benzophenones / pharmacology*
  • Catechol O-Methyltransferase / genetics*
  • Catechol O-Methyltransferase Inhibitors
  • Cognition / drug effects
  • Cognition / physiology*
  • Cohort Studies
  • Cross-Over Studies
  • DNA Mutational Analysis
  • Dopamine / metabolism
  • Double-Blind Method
  • Enzyme Inhibitors / pharmacology
  • Genetic Testing
  • Genotype
  • Humans
  • Male
  • Memory, Short-Term / drug effects
  • Memory, Short-Term / physiology*
  • Methionine / genetics
  • Neural Inhibition / drug effects
  • Neural Inhibition / genetics
  • Nitrophenols / pharmacology*
  • Polymorphism, Genetic / genetics*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Sensory Gating / drug effects
  • Sensory Gating / physiology*
  • Tolcapone
  • Valine / genetics
  • Young Adult


  • Benzophenones
  • Catechol O-Methyltransferase Inhibitors
  • Enzyme Inhibitors
  • Nitrophenols
  • Methionine
  • Tolcapone
  • Catechol O-Methyltransferase
  • Valine
  • Dopamine