Serotonin Depletion Induces ‘Waiting Impulsivity’ on the Human Four-Choice Serial Reaction Time Task: Cross-Species Translational Significance

Abstract

Convergent results from animal and human studies suggest that reducing serotonin neurotransmission promotes impulsive behavior. Here, serotonin depletion was induced by the dietary tryptophan depletion procedure (TD) in healthy volunteers to examine the role of serotonin in impulsive action and impulsive choice. We used a novel translational analog of a rodent 5-choice serial reaction time task (5-CSRTT)-the human 4-CSRTT-and a reward delay-discounting questionnaire to measure effects on these different forms of 'waiting impulsivity'. There was no effect of TD on impulsive choice as indexed by the reward delay-discounting questionnaire. However, TD significantly increased 4-CSRTT premature responses (or impulsive action), which is remarkably similar to the previous findings of effect of serotonin depletion on rodent 5-CSRTT performance. Moreover, the increased premature responding in TD correlated significantly with individual differences on the motor impulsivity subscale of the Barratt Impulsivity Scale. TD also improved the accuracy of performance and speeded responding, possibly indicating enhanced attention and reward processing. The results suggest: (i) the 4-CSRTT will be a valuable addition to the tests already available to measure impulsivity in humans in a direct translational analog of a test extensively used in rodents; (ii) TD in humans produces a qualitatively similar profile of effects to those in rodents (ie, enhancing premature responding), hence supporting the conclusion that TD in humans exerts at least some of its effects on central serotonin; and (iii) this manipulation of serotonin produces dissociable effects on different measures of impulsivity, suggesting considerable specificity in its modulatory role.

Exaggerated Waiting Impulsivity Associated with Human Binge Drinking, and High Alcohol Consumption in Mice

“…Increased premature responding in BD subjects was accompanied by attentional impairments, revealed as more omitted trials, and lower accuracy of detection in the dual-task condition. Others have recently independently developed a similar human analog of the 5CSRTT to measure waiting impulsivity Worbe et al, 2014), and have found parallels with rodent performance in substance abusers, and following neurochemical manipulations, suggesting close parallels between measures of waiting impulsivity in humans and rodents.…”

The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs

“…Earlier findings that global 5-HT depletions with the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) increase impulsivity in rodents measured by increased premature responses on the 5-CSRTT have been translated to humans with 5-HT depletions induced by the dietary tryptophan depletion paradigm in healthy volunteers administered an analogous four-choice serial reaction time test (Harrison et al, 1997;Winstanley et al, 2004;Worbe et al, 2014). Similarly, global brain 5-HT depletions in rats with intraventricular 5,7-DHT lesions also increase the response rate with a clear leftward shift in the IRT distribution in subjects responding under a DRL 72-second schedule (Jolly et al, 1999).…”

The Role of Serotonin in Aggression and Impulsiveness

“…By this means, it has been concluded that central serotonin levels are related to waiting impulsivity rather than stopping impulsivity. Interestingly, it has been determine that tryptophan-depleted individuals had an increase in motivation and accuracy in compliance with individuals who do not have this depletion [53,54].…”