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Paul Harrison and colleagues awarded 3-year MRC grant to study the effects of tolcapone, a COMT inhibitor, on behaviour and brain activity

Paul Harrison, Liz Tunbridge, Clare Mackay, Cath Harmer,  Robert Rogers, and Emily Holmes (now at the MRC Cognition and Brain Science Unit, Cambridge) have received a 3-year MRC grant to study the effects of tolcapone, a COMT inhibitor, on behaviour and brain activity, and how these effects interact with stress and a person’s genetic make up. COMT is an enzyme which regulates cortical dopamine. The work will build upon a recent Wellcome Trust-funded project which showed that tolcapone affects working memory and risk taking, but in opposite directions depending on COMT genotype (Farrell et al, Biol Psychiatry 2012; 71: 538-544) . That is, people with the high activity form of the gene (‘COMT-Val’) show improvements in memory and become risk averse in response to the drug, whereas people with the low activity form (‘COMT-Met’) have worsened memory and become more risk taking.  The new grant funds two studies. In the first, we will test people in a wider range of cognitive and emotional tasks, to see how widespread is the genotype influence on response to tolcapone.  In the second study, we will acutely stress people before testing them, since there are reasons to believe that stress will interact with COMT genotype to alter the effect of tolcapone. This study will be conducted in an MRI scanner so that brain activity can also be measured. The project has two goals. First, to understand better the role of COMT in brain function and how this is impacted upon by stress. Second, COMT inhibitors are used in Parkinson’s disease and are being trialled in other disorders, and we hope to shed light on how their therapeutic use may be influenced by genetic and environmental factors.


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