Effect of tryptophan depletion on conditioned threat memory expression: role of intolerance of uncertainty

Abstract

BackgroundResponding emotionally to danger is critical for survival. Normal functioning also requires flexible alteration of emotional responses when a threat becomes safe. Aberrant threat and safety learning occurs in many psychiatric disorders including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and schizophrenia, where emotional responses can persist pathologically. Whilst there is evidence that threat and safety learning can be modulated by the serotonin systems, there have been few studies in humans. We addressed a critical clinically relevant question: How does pharmacological lowering of serotonin affect the retention of conditioned threat memory? MethodsForty-seven healthy participants underwent threat conditioning on Day 1 followed by an extinction session. Emotional responding was assessed by the skin conductance response (SCR). On Day 2, we employed acute dietary tryptophan depletion to lower serotonin temporarily, in a double-blind placebo-controlled randomized between-groups design. We then tested for the return of conditioned threat memory spontaneous recovery). We also measured self-reported intolerance of uncertainty, known to modulate threat memory expression. ResultsThe expression of emotional memory was attenuated in participants who had undergone tryptophan depletion. Individuals who were more intolerant of uncertainty showed even greater attenuation of emotion following depletion. ConclusionsThese results support the view that serotonin is involved in predicting aversive outcomes and refine our understanding of the role of serotonin in the persistence of emotional responsivity, with implications for individual differences in vulnerability to psychopathology.

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

“…'Cold' cognition Our results showed no significant effects on any measures of 'cold' cognition, thus contrasting with some of our previous data obtained following acute administration [20]. Previous studies manipulating serotonin acutely have shown alterations in both 'cold' and 'hot' cognitive measures [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. However, it is important to note that our study examined SSRI administration over a longer time period, which has not previously been much studied in the context of human cognition.…”

“…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].…”

“…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]. Effects of ATD have also been seen on reinforcement behaviour [13], reversal learning [9,14], learning and memory [15], affective and social cognition [9,16,17] and moral judgement [18]. Studies examining the acute administration of SSRIs have shown impaired probabilistic learning [19,20], and impaired cognitive flexibility [20], but increased long-term memory recall [21], emotion recognition [22], and harm aversion for moral judgements [23].…”

I doubt it is safe: A meta-analysis of self-reported intolerance of uncertainty and threat extinction training

“…In keeping with a variety of metrics used in the literature to capture the process of threat extinction (57) While there is some interdependence between the different SCR difference scores, organising the SCR data in this manner allows for the assessment of threat and safety discrimination overall, and across time (57). For 4 experiments, only the early extinction training metric was analysed (64,65,69,70). This was due to these studies having too few extinction learning trials to examine SCR across the whole phase, during late extinction, and comparing early versus late extinction (i.e., the studies only had 9 or 10 total trials per CS type).…”