Catechol-O-methyltransferase (COMT) is one of several important enzymes for metabolism of dopamine in the brain. The COMT Val(158)Met polymorphism has been found to influence enzyme activity and working memory function in human subjects. An inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype.
In this study 34 COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) male subjects were given a single 200-mg dose of the COMT inhibitor tolcapone or placebo. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on a test of working memory. Tolcapone had opposite effects in the two genotype groups: it worsened test performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Genotype-dependent effects on risky decision making in a gambling task were also seen. The authors concluded that COMT inhibitor enhancement or impairment of working memory can be influenced by a polymorphism in its target gene. The results also supported the inverted-U model of dopamine function. The findings are of clinical relevance since COMT inhibitors are used in the treatment of Parkinson’s disease and are under evaluation in schizophrenia and other disorders.
Farrell SM, Tunbridge EM, Braeutigam S, Harrison PJ: COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition. Biological Psychiatry 71(6): 538-544 (2012).
