Costello, H. | Search bioRxiv

bioRxiv2025

Differential effects of dopamine and serotonin on reward and punishment processes in humans: A systematic review and meta-analysis

ImportanceTo 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. ObjectiveTo 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 SourcesOvid 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 SelectionStudies 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 SynthesisStandardized 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 Collaborations tool), moderators, heterogeneity, and publication bias were also assessed. Main Outcome(s) and Measure(s)Performance on reward/punishment processing tasks. ResultsIn total, 68 dopamine and 39 serotonin studies in healthy volunteers were included (Ndopamine=2291, Nplacebo=2284; Nserotonin=1491, Nplacebo=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 RelevancePharmacological 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 pointsO_ST_ABSQuestionC_ST_ABSDo pharmacological manipulations of dopamine and serotonin affect components of reinforcement learning in humans? FindingsUpregulating 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. MeaningPharmacological 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.

neuroscience↗

bioRxiv2024

Depression in Parkinson's disease is associated with dopamine unresponsive reduced reward sensitivity during effort-based decision making

Willingness to exert effort for a given goal is dependent on the magnitude of the potential rewards and effort costs of an action. Such effort-based decision making is an essential component of motivation, in which the dopaminergic system plays a key role. Depression in Parkinsons disease (PD) is common, disabling and has poor outcomes. Motivational symptoms such as apathy and anhedonia, are prominent in PD depression and related to dopaminergic loss. We hypothesised that dopamine-dependent disruption in effort-based decision-making contributes to depression in PD. In the present study, an effort-based decision-making task was administered to 62 patients with PD, with and without depression, ON and OFF their dopaminergic medication across two sessions, as well as to 34 patients with depression and 29 matched controls on a single occasion. During the task, on each trial, participants decided whether to accept or reject offers of different levels of monetary reward in return for exerting varying levels of physical effort via grip force, measured using individually calibrated dynamometers. The primary outcome variable was choice (accept/decline offer), analysed using both logistic mixed-effects modelling and a computational model which dissected the individual contributions of reward and effort on depression and dopamine state in PD. We found PD depression was characterised by lower acceptance of offers, driven by markedly lower incentivisation by reward (reward sensitivity), compared to all other groups. Within-subjects analysis of the effect of dopamine medication revealed that, although dopamine treatment improves reward sensitivity in non-depressed PD patients, this therapeutic effect is not present in PD patients with depression. These findings suggest that disrupted effort-based decision-making, unresponsive to dopamine, contributes to PD depression. This highlights reward sensitivity as a key mechanism and treatment target for PD depression that potentially requires non-dopaminergic therapies.

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