Working memory capacity is extremely limited and individual differences are heritable to a considerable extent. In the search for a better understanding of the exact genetic underpinnings of working memory, most research has focused on functional gene variants involved in the metabolism of the neurotransmitter dopamine. Recently, there has been investigation of genes related to other neurotransmitter systems such as acetylcholine. The potential relevance of a polymorphism located in the gene coding for the alpha4 subunit of the nicotinic acetylcholine receptor (rs#1044396) has been discussed with respect to working memory, but empirical investigations have provided mixed results. However, pharmacological studies in both rodents and humans have shown that the effect of nicotinic agonists on cognitive functions is mediated by dopamine. We therefore hypothesized that such an interaction can be found on a molecular genetic level as well. In order to test this hypothesis, we genotyped 101 healthy subjects for rs#1044396 and three functional polymorphisms on the dopamine d2 receptor gene (rs#1800497, rs#6277, rs#2283265). These subjects performed a visuospatial working memory task in which memory load was systematically varied. We found a significant interaction between rs#1044396 and a haplotype block covering all three dopaminergic polymorphisms on working memory capacity. This effect only became apparent on higher levels of working memory load. This is the first evidence from a molecular genetic perspective that these two neurotransmitter systems interact on cognitive functioning. The results are discussed with regard to their implication for working memory theories and their clinical relevance for treatment of substance abuse and schizophrenia.

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