Abstract
Serotonin is involved in updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, autonomic responses 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 autonomic inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes, respectively, in two independent experiments (N = 97). Experiment 1 assessed instrumental (stimulus-response-outcome) reversal learning whereby individuals learned through trial and error which action was most optimal for obtaining reward or avoiding punishment initially, and the contingencies subsequently reversed serially. Experiment 2 examined Pavlovian (stimulus-outcome) reversal learning assessed by the skin conductance response: one innately threatening stimulus predicted receipt of an uncomfortable electric shock and another did not; these contingencies swapped in a reversal phase. Upon depleting the serotonin precursor tryptophan—in a double-blind randomised placebo-controlled design—healthy volunteers showed impairments in updating both actions and autonomic responses to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. Initial Pavlovian conditioning, moreover, which involved innately threatening stimuli, was potentiated by depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.
Highlights
Serotonin (5-HT; 5-hydroxytryptamine) is classically involved in responding to negative events, is increasingly recognised to be engaged in reward learning, and is important for adapting previously learned responses to reflect new environmental circumstances [1,2,3,4,5,6,7,8,9,10]
In post-traumatic stress disorder (PTSD) and panic disorder, several studies suggest flexibility, we addressed whether depleting serotonin would an increased sensitivity of the 5-HT2C receptor as determined potentiate initial Pavlovian conditioning when employing innately through pharmacological challenge [33, 42, 43]
We have provided convergent evidence from two independent reported in obsessivecompulsive disorder (OCD) [11] and healthy humans under stress [117], and experiments that serotonin depletion effected by acute dietary align with other studies of serotonin in rats, monkeys, and humans tryptophan depletion impairs human reversal learning in both the [56, 69, 113]
Summary
Serotonin (5-HT; 5-hydroxytryptamine) is classically involved in responding to negative events, is increasingly recognised to be engaged in reward learning, and is important for adapting previously learned responses to reflect new environmental circumstances [1,2,3,4,5,6,7,8,9,10]. We studied healthy human volunteers to examine the effects of lowering serotonin synthesis on cognitive flexibility assessed by instrumental and Pavlovian reversal learning. Whereby an initial contingency is learned and subsequently reverses, have revealed both Pavlovian and instrumental reversal learning deficits in obsessivecompulsive disorder (OCD), a prototypical disorder of cognitive inflexibility [11, 12]. Pavlovian reversal deficits have been observed in post-traumatic stress disorder (PTSD) [13]. Non-reversal aberrations in Pavlovian threat and safety learning have been reported in OCD [18, 19], schizophrenia [20, 21], PTSD [22, 23], and other anxiety disorders [22, 24, 25]
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