a b s t r a c tDecision-making plays an important role in everyday life and is often disturbed in psychiatric conditions affected by the common human serotonin transporter promoter length polymorphism (5-HTTLPR). This raises the hypothesis that decision-making is modulated by the serotonergic system, but currently it is unclear how the 5-HTTLPR affects central serotonergic functioning. We tested healthy human volunteers genotyped for the 5-HTTLPR in the Iowa Gambling Task (IGT), which is one of the most frequently used neuropsychological tasks to assess decision-making. Furthermore, we tested female homozygous (SERT À/À ) and heterozygous (SERT þ/À ) serotonin transporter knockout rats in a rodent version of the IGT.Women homozygous for the short (s) allele of the 5-HTTLPR were found to choose more disadvantageously than women homozygous for the long allele of the 5-HTTLPR as the IGT progressed. In the rat, SERT À/À and SERT þ/À were associated with advantageous decision-making compared to SERT þ/þ as the IGT progressed. Combining the human and rat observations, we show that SERT dosage affects the maintenance of a once established choice option, irrespective of the choice (advantageous or disadvantageous) that has been made. We postulate that the SERT-mediated effects relate to deficits in the processing of choice outcome to guide subsequent choices in this gamble-based test, and that SERT À/À and SERT þ/À rodent models in combination with studies in humans can be used to provide insight in the modulatory effects of 5-HTTLPR.

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