Improvement of Prepulse Inhibition and Executive Function by the COMT Inhibitor Tolcapone Depends on COMT Val158Met Polymorphism

Abstract

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. Neuropsychopharmacology (2008) 33, 3058-3068; doi:10.1038/npp.2008 published online 4 June 2008 Keywords: prepulse inhibition; sensorimotor gating; prefrontal cortex; dopamine; cognition; working memory INTRODUCTIONThe enzyme catechol-O-methyltransferase (COMT) is the main catabolic pathway by which dopamine (DA) is removed from the cortical synaptic cleft in humans (Karoum et al, 1994). Indeed, COMT is found in high concentrations in the cortex relative to subcortical regions (Matsumoto et al, 2003) consistent with the absence of functional DA transporters in cortical areas such as the prefrontal cortex (PFC) and hippocampus (Mazei et al, 2002). The Val158Met polymorphism in the COMT gene leads to an amino-acid substitution (valine (Val) to methionine (Met)) and results in the Met/Met variant showing 40% less enzymatic activity than the Val/Val (Chen et al, 2004). There is now abundant evidence (reviewed in Harrison and Weinberger, 2005;Tunbridge et al, 2006) that Met158 allele loading is dose dependently associated with superior performance on a variety of cognitive tests assessing executive function, as well as prefrontal physiology as assessed by neuroimaging. The evidence suggests that PFC DA facilitates 'focusing and stabilizing' activity in PFC networks during executive cognition, ie enhances prefrontal physiologic 'efficiency' by reduction of prefrontal noise (Cools et al, 2002;Mattay et al, 2002Mattay et al, , 2003.Prepulse inhibition (PPI) is thought...

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