Dopamine and serotonin differentially associated with reward and punishment processes in humans: A systematic review and meta-analysis
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Importance
To support treatment assignment, mechanistic biomarkers should be selectively sensitive to specific interventions. Here, we examine whether different components of reinforcement learning in humans satisfy this necessary precondition. We focus on pharmacological manipulations of dopamine and serotonin that form the backbone of first-line management of common mental illnesses such as depression and anxiety.
Objective
To perform a meta-analysis of pharmacological manipulations of dopamine and serotonin and examine whether they show distinct associations with reinforcement learning components in humans.
Data Sources
Ovid MEDLINE/PubMed, Embase, and PsycInfo databases were searched for studies published between January 1, 1946 and January 19, 2023 (repeated April 9, 2024, and October 15, 2024) investigating dopaminergic or serotonergic effects on reward/punishment processes in humans, according to PRISMA guidelines.
Study Selection
Studies reporting randomized, placebo-controlled, dopaminergic or serotonergic manipulations on a behavioral outcome from a reward/punishment processing task in healthy humans were included.
Data Extraction and Synthesis
Standardized mean difference (SMD) scores were calculated for the comparison between each drug (dopamine/serotonin) and placebo on a behavioral reward or punishment outcome and quantified in random-effects models for overall reward/punishment processes and four main subcategories. Study quality (Cochrane Collaboration’s tool), moderators, heterogeneity, and publication bias were also assessed.
Main Outcome(s) and Measure(s)
Performance on reward/punishment processing tasks.
Results
In total, 68 dopamine and 39 serotonin studies in healthy volunteers were included (N dopamine =2291, N placebo =2284; N serotonin =1491, N placebo =1523). Dopamine was associated with an increase in overall reward (SMD=0.18, 95%CI [0.09 0.28]) but not punishment function (SMD=-0.06, 95%CI [−0.26,0.13]). Serotonin was not meaningfully associated with overall punishment (SMD=0.22, 95%CI [−0.04,0.49]) or reward (SMD=0.02, 95%CI [−0.33,0.36]). Importantly, dopaminergic and serotonergic manipulations had distinct associations with subcomponents. Dopamine was associated with reward learning/sensitivity (SMD=0.26, 95%CI [0.11,0.40]), reward discounting (SMD=-0.08, 95%CI [−0.14,-0.01]) and reward vigor (SMD=0.32, 95%CI [0.11,0.54]). By contrast, serotonin was associated with punishment learning/sensitivity (SMD=0.32, 95%CI [0.05,0.59]), reward discounting (SMD=-0.35, 95%CI [−0.67,-0.02]), and aversive Pavlovian processes (within-subject studies only; SMD=0.36, 95%CI [0.20,0.53]).
Conclusions and Relevance
Pharmacological manipulations of both dopamine and serotonin have measurable associations with reinforcement learning in humans. The selective associations with different components suggests that reinforcement learning tasks could form the basis of selective, mechanistically interpretable biomarkers to support treatment assignment.
Key points
Question
Do pharmacological manipulations of dopamine and serotonin affect components of reinforcement learning in humans?
Findings
Upregulating dopamine is associated with increased reward learning/sensitivity and reward response vigor, and decreased reward discounting. Upregulation of serotonin is associated with increased punishment learning/sensitivity and decreased reward discounting.
Meaning
Pharmacological manipulations of dopamine and serotonin have dissociable associations with different components of reinforcement learning. This forms a necessary basis for the development of selective markers for treatment assignment.
