One reason for the interest in working memory is because it may reflect function in the meso-cortical dopamine (DA) pathway. Experimental manipulation of DA metabolism by pharmacological challenge in humans and animals supports the assumption that the DA system is involved in cognition: reduced DA transmission in the rat prefrontal cortex impairs cortical-dependent cognition (Jentsch et al. 1997), administration of a selective inhibitor of COMT improves cognitive function (including working memory) in patients with Parkinson’s disease (Gasparini et al. 1997), while injection of D1 antagonists into the dorsolateral prefrontal cortex impairs tasks that require working memory (Sawaguchi & Goldman-Rakic, 1991; Williams & Goldman-Rakic, 1995). As mentioned above, COMT plays an important role in DA metabolism in the frontal cortex and the Val/Met polymorphism is a critical factor in determining COMT efficiency: the Val isoform has higher activity which may lead to lower synaptic DA levels in the prefrontal cortex (Chen et al. 2004). Thus there is a strong prior hypothesis that implicates DA regulation in prefrontal cortical function, and particularly that variation in COMT genotype could be associated with an
