Search

Catechol-O-methyltransferase (COMT) metabolizes catechols, notably dopamine. The COMT Val158Met polymorphism influences its enzyme activity, and multiple neural correlates of this genotype on dopaminergic phenotypes have been reported, particularly with regards to working memory. COMT activity can also be regulated pharmacologically by COMT inhibitors. The ‘inverted-U’ relationship between dopamine signalling and cognitive performance predicts that the effects of COMT inhibition will differ according to COMT genotype. The goal of this thesis was to better understand COMT’s impact on brain function and behaviour. Here, 33 subjects homozygous for COMT Val158 (‘Val homozygotes’) and 34 homozygous for COMT Met158 (‘Met homozygotes’) were randomly assigned, double-blind, to a single dose of the brain-penetrant COMT inhibitor tolcapone (200mg) or placebo. They completed the N-back task of working memory, an emotional face processing task, and a gambling task, in a magnetoencephalography (MEG) scanner, allowing both behavioural performance and neural activity to be investigated. The data presented in this thesis confirm that COMT activity influences performance on, and neural activity during, the N-back task, in a way consistent with the inverted-U model of dopamine function. The effect on risky decision making is novel, and indicates that COMT plays roles in domains beyond working memory, and that such domains may also follow an inverted-U. Neural activity during the faces task and the gambling task also show COMT-modulated differences. The behavioural results show that the direction of effect of a drug can be influenced by sequence variation in its target gene. They are of translational relevance, since COMT inhibitors are used in the adjunctive treatment of Parkinson’s disease and are under evaluation in schizophrenia and other disorders. The MEG data show that for the three tasks, there are effects of Val158Met genotype, of tolcapone, and their interaction, on neural activity (for example, the P300 during N-back), revealing a complex temporal and spatial pattern which sheds some light on the neural processing underlying these tasks and their previously reported fMRI correlates.