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

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.

Fig. 1. Experiment 1 task schematic.

TOP: The three rectangles with coloured frames represent three example trials presented in the acquisition phase. Purple ovals symbolise the button boxes. Question marks signify the need to learn the correct hand-colour association by trial and error. Downward pointing arrows indicate the correct hand and button response for that trial. BOTTOM: Curved arrows signify the reversal of colour-hand contingencies, which occurred three times.

Fig. 2. Instrumental reversal learning performance by block.

More trials to criterion signifies worse performance. Asterisks represent significance at p < 0.05. Error bars represent ±1 standard error of the mean. a Impairment in Reversal 2 of the reward-punishment condition (R-P). b Impairments in Reversals 1 and 2 of the reward-neutral condition (R-N). c No differences in instrumental performance in the punishment-neutral condition (P–N). d No differences in instrumental performance in the neutral-neutral condition (N–N).

Fig. 3. Relationship between extent of depletion and instrumental reversal learning performance.

a Reward-punishment (R-P) condition. b Reward-neutral (R-N) condition. Both correlations were significant. ΔTRP:LNAA is the change in the ratio of tryptophan to large neutral amino acids; 0 indicates no change. A greater decrease (post-depletion minus pre-depletion blood plasma results) in the TRP:LNAA ratio indicates a more extensive depletion (more negative y-axis values). Reversal learning is indexed here as the number of trials to criterion in the second reversal block. Increasing x-axis values represent more trials to criterion and thus worse reversal performance. Shading indicates ±1 standard error (SE).

Fig. 4. Pavlovian acquisition and reversal SCR data (Experiment 2), visualised in two different ways.

Error bars represent ±1 standard error (SE). a Difference scores of CS+ minus CS−, indicative of the extent of discrimination learning to the two stimuli. Asterisks (*) indicate significance at p < 0.05; double asterisks (**) denote significance at p < 0.01. b All stimuli displayed separately. CSpACQ = (initial) CS+ during acquisition; CSmACQ = (initial) CS− during acquisition; CSpREV = (new) CS+ during reversal; CSmREV = (new) CS– during reversal.

Fig. 5. Experiment 2.

Relationship between extent of depletion and degree of Pavlovian reversal learning impairment. The correlation was significant. ΔTRP:LNAA is the change in the ratio of tryptophan to large neutral amino acids; y = 0 indicates no change. A greater change (post-depletion blood minus pre-depletion results) in the TRP:LNAA ratio indicates a more extensive depletion (more negative y-axis values). Reversal learning is indexed here as the difference score between CS+ and CS− in the reversal phase. Increasing x-axis values represent better discrimination learning assessed by SCR between the CS+ and CS− in the reversal phase (i.e. better reversal learning). Shading indicates ±1 standard error (SE).