Depleting Serotonin Impairs Reversal Learning

Post by Elisas Guma

What's the science?

Serotonin (5-hydroxytryptamine or 5-HT) is a key neurotransmitter in the brain, important for our ability to adapt previously learned responses to a changing environment — also known as reversal learning. Impairments in reversal learning and serotonergic dysfunction have both been reported in numerous neuropsychiatric disorders including obsessive-compulsive disorder (OCD), post-traumatic stress disorder, schizophrenia, and addictions. Despite its broad clinical relevance, few studies have investigated the impact of serotonin on behavioural adaptation in humans. This week in Molecular Psychiatry Kanen and colleagues sought to experimentally test the effect of serotonin depletion on reversal learning ability in healthy humans.

How did they do it?

Healthy volunteer participants were recruited to participate in one of two different experiments and randomly assigned to either acute tryptophan depletion (a serotonin precursor) or placebo in a randomized, double-blind, between-groups design. Tryptophan depletion was attained via consumption of a drink containing the essential amino acids but no tryptophan, while the placebo group’s drink included tryptophan. To ensure serotonin levels were depleted, blood plasma samples were collected.

In Experiment 1, 69 healthy participants were tested in an instrumental reversal learning task. Briefly, participants performed a series of trials in which they had to press a button with the correct finger based on the colour of the screen and the presence of a dot in one of five boxes (ex: red screen and dot in 4th box = right ring finger). In total, participants completed 4 rounds - 1 round of 20 trials of acquisition,  and three rounds of 20 trials of reversal learning where the rule was changed (ex: red screen and 4th dot = left index finger). Each of the 4 rounds was assigned a different level of reward salience (intensity). For the reward-punishment condition participants heard a cha-ching sound for correct answers (reward) and an aversive buzzer for incorrect answers (punishment). There were also reward-neutral (only the cha-ching sound), neutral-punishment (only the aversive buzzer), and neutral-neutral conditions.

Experiment 2 examined reversal learning in the Pavlovian domain. Participants were presented with two threatening faces, one of which was sometimes paired with electric shock (a level chosen by the participant to be uncomfortable but not painful), while the other was not. In the reversal learning phase the originally conditioned face became safe, and the initially safe face was paired with a shock.

What did they find?

For the instrumental learning task (Experiment 1), the authors found that participants who had received acute tryptophan depletion required more trials to criterion than the placebo group for the reversal in the most salient condition (reward-punishment condition). Further, in the reward-neutral condition, they also observed a deficit for the acute tryptophan depleted group, while no deficit was observed in the punishment-neutral or neutral-neutral conditions. Importantly, the magnitude of tryptophan depletion was related to the magnitude of reversal impairments in the reward-punishment and reward-neutral conditions.

In the Pavlovian acquisition (Experiment 2), the acute tryptophan depleted group also displayed reversal learning impairments, as they were not able to learn the association between face and shock had changed.

What's the impact?

This study provides evidence from two independent experiments that serotonin depletion impairs human reversal learning in both instrumental and Pavlovian domains. These deficits have not been well captured previously in humans, however, the findings are in line with observations made in other experimental animal studies, as well as in individuals with OCD. Understanding the role of serotonin in reversal learning, a fundamental learning process, may provide important insight into our understanding and development of treatment for conditions in which reversal learning is impaired.

Kanen JW et al. Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans. Molecular Psychiatry (2021). Access the original scientific publication here.