Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Abstract

Serotonin is implicated in aversive processing and updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, emotional reactions to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and emotional inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes in two independent experiments (N = 97), using instrumental and aversive Pavlovian reversal learning paradigms, respectively.Upon depleting the serotonin precursor tryptophan -in a double-blind randomised placebocontrolled design -healthy volunteers showed impairments in updating both behaviour and emotion to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

A self-adjusting, progressive shock strength procedure to investigate resistance to punishment: Characterization in male and female rats

“…Therefore, the PSS appears particularly fit to stricter ethical standards of animal research that are required by our societies. Finally, the individual calibration of shock levels of the PSS is conceptually similar to what is commonly done in investigate the mechanisms of punishment and compulsivity in humans (Apergis-Schoute et al, 2017;Kanen et al, 2021;Kim and Anderson, 2020) which can increase the translational validity of this procedure. Shock sessions were repeated but infrequent and sparse.…”

“…Procedures that adjust the level of shock to individual behavior may allow a more precise measure of resistance to punishment and be more in accordance with ethical standards because punishment is titrated within a range close to the individual's threshold, only exceeding it infrequently and by a small amount. In addition, they would resemble procedures commonly used to investigate the effects of punishment in humans, in which shock levels are calibrated individually (Apergis-Schoute et al, 2017;Kanen et al, 2021;Kim and Anderson, 2020).…”

Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study

“…In humans, the modulatory effects of serotonin on cognition have largely been examined through acute dietary tryptophan depletion (ATD) [8][9][10][11][12][13][14][15][16][17][18], or through acute SSRI administration [19][20][21][22][23]. ATD has been shown to affect measures of both 'cold' (rational and non-emotional), and 'hot' (social and emotional) cognition [13][14][15][16][17][18].…”

“…In humans, the modulatory effects of serotonin on cognition have largely been examined through acute dietary tryptophan depletion (ATD) [8][9][10][11][12][13][14][15][16][17][18], or through acute SSRI administration [19][20][21][22][23]. ATD has been shown to affect measures of both 'cold' (rational and non-emotional), and 'hot' (social and emotional) cognition [13][14][15][16][17][18]. Specifically, ATD induces 'waiting' impulsivity and impulsive behaviours, impairs goal-directed behaviour and shifts behavioural control toward habitual responding in appetitive conditions, but goal-directed in aversive conditions [10][11][12].…”

Psychedelics, Sociality, and Human Evolution

“…Under such circumstances, tryptamine psychedelics (e.g., DMT, psilocybin) could have provided an ideal substitute for a fundamental bioactive compound that is hard for the body to produce, effectively mimicking 5-HT’s structure and function ( Nichols, 2016 ). Self-medication with psilocybin mushrooms would have ameliorated the costs associated with impairment of serotonergic neural signaling, involving depressed mood ( Jenkins et al, 2016 ), increased stress vulnerability ( Sachs et al, 2015 ), and cognitive inflexibility ( Kanen et al, 2020 ).…”