The Impact of Tryptophan Depletion and 5-HTTLPR Genotype on Passive Avoidance and Response Reversal Instrumental Learning Tasks

Abstract

Transient reductions in serotonin levels during tryptophan depletion (TD) are thought to impair reward processing in healthy volunteers, while another facet of the serotonergic system, the serotonin transporter (5-HTTLPR) short allele polymorphism, is implicated in augmented processing of aversive stimuli. We examined the impact and interactions of TD and the serotonin promoter polymorphism genotype on reward and punishment via two forms of instrumental learning: passive avoidance and response reversal. In this study, healthy volunteers (n ¼ 35) underwent rapid TD or control procedures and genotyping (n ¼ 26) of the 5-HTTLPR for long and short allele variants. In the passive avoidance task, tryptophan-depleted volunteers failed to respond sufficiently to rewarded stimuli compared to the control group. Additionally, long allele homozygous individuals (n ¼ 11) were slower to learn to avoid punished stimuli compared to short allele carriers (n ¼ 15). TD alone did not produce measurable deficits in probabilistic response reversal errors. However, a significant drug group by genotype interaction was found indicating that in comparison to short allele carriers, tryptophan-depleted individuals homozygous for the long allele failed to appropriately use punishment information to guide responding. These findings extend prior reports of impaired reward processing in TD to include instrumental learning. Furthermore, they demonstrate behavioral differences in responses to punishing stimuli between long allele homozygotes and short allele carriers when serotonin levels are acutely reduced.

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…89,90 On the other hand, among individuals without personal history of depression, the effect of TD is smaller, includes changes in anxiety, punishment sensitivity and motivation rather than mood and is more pronounced among ss homozygotes. [91][92][93][94] Neumeister and colleagues 90 proposed a model explaining this apparent interaction of 5-HTTLPR with personal history of depression by differential activity of pre-and postsynaptic 5-HT1A and 5-HT1B receptors.…”

The Roles of Dopamine and Serotonin in Decision Making: Evidence from Pharmacological Experiments in Humans

“…Thus, carriers of the ss allele of the 5-HTTPLR gene have shown enhanced attention toward probability cues during the performance of a risky choice task compared with carriers of the ll allele (Roiser et al, 2006), fewer risky choices in a financial investment task (Kuhnen and Chiao, 2009), and smaller impairments in probabilistic reversal tasks following tryptophan depletion (Finger et al, 2007), especially under aversive reinforcement conditions (Blair et al, 2008). Notably, female ss carriers have also shown poorer decisions under conditions of decision ambiguity (Stoltenberg and Vandever, 2010), poor performance of the Iowa gambling game compared with carriers of the ll allele (Homberg et al, 2008), and especially in OCD samples (da Rocha et al, 2008).…”

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

“…These include the control of many complex behaviors such as aggression, impulsive behavior, decision making, responsiveness to punishment and aversive signaling or anxiety (Carver and Miller, 2006;Cools et al, 2008;Dayan and Huys, 2009;Lucki, 1998;Rogers, 2011). Accordingly, serotonergic dysregulation during development and/or adulthood has been associated with many psychiatric disorders with diverse psychopathology (Carver and Miller, 2006;Finger et al, 2007;Geyer and Vollenweider, 2008;Gordon and Hen, 2004;Mann, 2003;Pardo and Eberhart, 2007;Zill et al, 2004).…”