In a recent study in Nature Communications, researchers increased synaptic serotonin through a selective serotonin-releasing agent (SSRA), fenfluramine, to investigate its impact on human behavior.
Study: Direct serotonin release in humans shapes aversive learning and inhibition. Image Credit: Vladimir Zotov/Shutterstock.com
Background
Neuroscience research concentrates on the function of central serotonin (5HT) in human behavior, specifically the impact of selective serotonin reuptake inhibitors (SSRIs). Serotonin is necessary for several actions, including eating, sexual function, and goal-directed cognition.
It is difficult to determine the causal relationship between increased synaptic 5-HT and behavior in humans via SSRIs due to SSRIs' complicated effects on 5-HT and colocalized neurotransmitter systems. A low dose of fenfluramine, approved for the treatment of Dravet epilepsy in 2020, directly and swiftly elevates synaptic 5-HT without altering extracellular dopamine concentrations in mood control areas.
About the study
In the present study, researchers investigated the effects of directly increasing synaptic serotonin (5-HT) with fenfluramine in humans, focusing on unpleasant processing, behavioral inhibition, and memory. They explored whether fenfluramine would cause behavior to differ from that observed with tryptophan deprivation.
The researchers included 53 individuals (mean age was 20 years, and 32 were female), randomized to receive 15 mg of fenfluramine hydrochloride twice daily (intervention group, n=26) or placebo (n=27) orally for eight days. They recruited eligible individuals between June 2021 and June 2022, excluding those who were pregnant, trying to become pregnant, lactating, and those with a recent history of recreational drug use. All participants were fluent in English and had body mass index (BMI) values ranging from 18 to 30.
Researchers used the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criteria and assessed cardiovascular, hepatic, and renal health to screen individuals. At baseline, participants completed various emotional and cognitive tasks and questionnaires. Researchers conducted immunoassays to measure fenfluramine-related salivary cortisol changes. They used linear mixed effects modes and the analysis of covariance (ANCOVA) to derive results.
At both visits (baseline and eight days later), participants filled out questionnaires assessing mood, anxiety, depression, subjective cognitive function, and adverse effects. The questionnaires included the Beck Depression Inventory-II (BDI), Perceived Deficit Questionnaire—Depression (PDQ-D), Spielberger State-Trait Anxiety Inventory (STAI-T), Positive and Negative Affect Schedule (PANAS), and Visual Analogue Scale (VAS).
Participants performed the Auditory Verbal Learning Task (AVLT), Affective Interference Go/No-Go Task, Verbal n-back task, Probabilistic instrumental learning task, Oxford Memory Task, and Contextual cueing task to measure implicit learning and visual search ability.
The AVLT task measured declarative memory encoding and retrieval; the Affective Interference Go/No-Go Task measured behavioral inhibition under affective interference; the Verbal n-back measured complex verbal working memory; the Probabilistic instrumental learning task measured reward and loss sensitivity during instrumental learning; the Oxford Memory Task measured visuospatial working memory; and the Contextual cueing task measured implicit learning and visual search ability.
Results
The study found that boosting synaptic serotonin lowers reinforcement sensitivity for unpleasant outcomes while enhancing behavioral inhibition, altering the bias toward impulse control during aversive interference or exposure to adverse emotional probes. Elevating synaptic serotonin improved memory for neutral verbal information.
Fenfluramine allocation lowered optimum choices in loss trials and reward circumstances, implying that elevated synaptic 5-HT reduced outcome sensitivity in loss trials. However, learning rates were not significantly different between groups. Fenfluramine administration also increased the time to option selection under loss conditions, showing a relative reduction in loss sensitivity.
Net increases in synaptic 5-HT reduce reinforcement sensitivity to loss outcomes, whereas 5-HT depletion enhances loss sensitivity. Fenfluramine administration enhanced response inhibition and cautious decision-making during go-trials, but there was no significant group effect on go-trial accuracy. Increasing synaptic 5-HT decreased choice impulsivity across all task circumstances, with the highest reduction noted when adverse emotional distractions were present.
The study discovered that increasing synaptic 5-HT enhances verbal memory processing; however, there was no significant group effect on the overall number of precisely recalled targets during sophisticated verbal working memory processing. The fenfluramine allocation led to faster recall of proper targets and greater total accuracy during delayed recall.
The team found no significant group effect for learning trials, word repeats, intrusions, or visuospatial working memory tasks. The placebo group outperformed the fenfluramine group, although not statistically significant. Gender did not influence the fenfluramine administration's impact on-task behavior.
Conclusion
The study found that increasing synaptic serotonin directly influences human behavior, impacting decision-making in unpleasant and neutral circumstances. Higher serotonin decreases sensitivity to loss consequences and enhances impulse control during behavioral inhibition in unfavorable situations. Higher serotonin improves behavioral inhibition by encouraging careful decision-making and memory retention in neutral conditions.
The study findings have implications for central serotonin function hypotheses and highlight the SSRA's potential as an experimental probe. Exploring its therapeutic potential might help us better grasp serotonin's involvement in human behavior and mental etiology.
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