The influence of stress and genotype on the response to a dopaminergic drug (Paul Harrison & Liz Tunbridge)
Tolcapone is an inhibitor of the dopamine-metabolizing enzyme catechol-o-methyltransferase (COMT), used in the adjunctive treatment of Parkinson’s disease. Our recent study (Farrell SM et al, Biological Psychiatry 2012; 71: 538-544), and others, show that it also has effects in healthy subjects on cognition and risk taking.
Interestingly, these effects depend on the person’s genotype. There is a common polymorphism in the gene, called V158M, which affects how active the enzyme is (and therefore sets the ‘tone’ of the cortical dopamine system). In individuals with the V158 genotype, tolcapone improves performance on a working memory task makes them more risk averse, but in individuals with the M158 form, the drug has the opposite effects: their working memory worsens, and they become more risk taking.
We want to follow up this striking pharmacogenetic finding, and to take another factor into account: acute stress – since there are reasons to predict that a stressor will differentially affect the two genotypes. We will genotype individuals, randomise them to tolcapone or placebo, and induce an acute stress using a traumatic film or a mental arithmetic task. They will then undertake cognitive, emotional, and reinforcement tasks whilst their stress response is measured. If funding permits, they will also undergo an fMRI scan. The work is translationally relevant, since novel COMT inhibitors are under development for a range of psychiatric disorders.
An ACL candidate would undertake the whole project and be responsible for its day-to-day running, whereas an ACF candidate would carry out part of the study (exact contribution to be discussed, depending on timing, expertise and interests).
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