Serotonergic mechanisms in levodopa-induced dyskinesia in Parkinson’s disease: circuit interactions and therapeutic opportunities

Levodopa (L-DOPA) remains the cornerstone of treatment for the motor symptoms of Parkinson’s disease (PD). However, its long-term use is frequently complicated by levodopa-induced dyskinesia (LID), which substantially limits its clinical benefit. Accumulating evidence suggests that, as nigrostriatal dopaminergic neurons progressively degenerate, serotonergic (5-hydroxytryptamine, 5-HT) neurons increasingly participate in the uptake, conversion, and release of L-DOPA. In the absence of intrinsic dopaminergic feedback regulation, this process may contribute to abnormal fluctuations in striatal dopamine signaling. This review examines the role of the 5-HT system in the pathophysiology of LID, with particular emphasis on how aberrant release of L-DOPA-derived dopamine, impaired spatiotemporal control of neurotransmission, and interactions with glial cells, cholinergic interneurons, and cortico-basal ganglia-related circuits may together amplify dyskinesia-associated maladaptive plasticity. We further summarize therapeutic strategies targeting serotonergic pathways, including 5-HT1A/1B receptor modulation, biased agonism, serotonin transporter-directed interventions, and pharmacological approaches involving other receptor subtypes, and compare their respective strengths and limitations in terms of efficacy, tolerability, and clinical translatability. Finally, we discuss several major challenges in the field, including the discrepancy between preclinical and clinical findings, patient heterogeneity, and the lack of robust biomarkers, and we highlight the need for precision interventions guided by molecular imaging and mechanism-based stratification. Overall, the 5-HT system represents an important entry point for linking the mechanistic basis of LID with therapeutic development, although its translational potential will require more rigorous mechanistic validation and stratified investigation.