Our work thus far has investigated the effects of altering serotonergic systems in humans using acute tryptophan depletion on behavioral performance during emotional processing tasks. Additionally, we have begun to determine how acute tryptophan depletions effects on emotional processing vary as a function of serotonin transporter genotype. Evidence suggests that manipulating serotonin using pharmacological challenges impacts different domains of emotional processing, and the effect of pharmacological challenges on emotional processing varies as a function of serotonin-related genotype (e.g., polymorphisms in the serotonin transporter). We found that both genotype and acute tryptophan depletion modulated dissociable components of emotional processing. Furthermore we found that the effects of altering serotonin transmission via tryptophan depletion were often genotype-dependent. For example, although tryptophan depletion in and of itself did not disrupt fear expression recognition, it did impair fear recognition in individuals who carried the short allele of the serotonin transporter gene. This indicates that genotype or changes in serotonergic transmission alone may not necessarily be sufficient to affect processing of social cues, but genotype may influence this domain of emotional processing when faced with a pharmacological challenge or when serotonin systems are altered. Another form of emotional processing that is important in the context of mood and anxiety disorders is reinforcement processing. Processing reward and punishment directly guides behaviors and decision making, and atypical reinforcement processing occurs in a variety of psychiatric conditions. When we began our studies, there was evidence suggesting that altering serotonin systems reduces responsivity to reward and increases sensitivity to punishment. Thus, we attempted to investigate these claims further to determine the role of serotonin in reinforcement processing. In a series of studies, we found that altering serotonin systems via acute tryptophan depletion altered reinforcement processing, and that this effect was, in some cases, genotype dependent. In one study, using an instrumental learning task, we found that tryptophan depletion impaired reward processing. Interestingly, individuals who were homozygous for the long version of the serotonin transporter gene responded differently to punishment than did carriers of the short version. Long homozygotes were slower to avoid the bad (punishment) stimuli than were short carriers. We also looked at the effects of tryptophan depletion on response reversal, which measures the ability to change ones response when a previously rewarded behavior becomes a punished behavior. We found that tryptophan-depleted long carriers were not as efficient at using negative feedback to guide appropriate responding compared to tryptophan-depleted short carriers. Long carriers were also less likely to maintain correct responding in the face of probabilistic punishment during tryptophan depletion than tryptophan-depleted s carriers and long carriers who received the placebo. To further explore the role of serotonin in sensitivity to reward and punishment, we investigated the effects of tryptophan depletion on a decision making task, which requires individuals to choose between two objects associated with different amounts of reward or punishment. We found that ATD altered sensitivity to punishment-related information and that sensitivity to punishment varied as a function of transporter genotype. Over the past 12 months, we have extended our previous work by examining the selective effects of tryptophan depletion on neural regions engaged in expression processing, emotional attention and reversal learning. While the data from the emotional attention and reversal learning paradigms is currently being processed, we have observed the effects of tryptophan depletion on reducing amygdala responsiveness (and the responsiveness of associated regions) to emotional expressions.
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|Blair, K S; Finger, E; Marsh, A A et al. (2008) The role of 5-HTTLPR in choosing the lesser of two evils, the better of two goods: examining the impact of 5-HTTLPR genotype and tryptophan depletion in object choice. Psychopharmacology (Berl) 196:29-38|