ArticleProceedings of the National Academy of Sciences of the United States of America2013
Serotonin spillover onto the axon initial segment of motoneurons induces central fatigue by inhibiting action potential initiation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers, 1 of them a synthesis that pooled it.
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Who cites it
71 citing papers in PubMed, 1 synthesis or guideline pooled it, 164 citations in OpenAlex.
- Effects of serotonergic pharmacological manipulation on exercise performance and central fatigue: a systematic review and three-level meta-analysis.Journal of the International Society of Sports Nutrition · 2026Pooled it
- 5-HTThe Journal of physiology · 2025Trial
- The neurobiological markers of acute alcohol's subjective effects in humans.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Trial
- Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions.The Journal of physiology · 2019Trial
- Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone.The Journal of physiology · 2017Trial
- Serotonergic modulation of motor subspace dynamics drives a sleep-independent quiescent state.eLife · 2026Article
- Axon Initial Segment: Structure, Biological Functions, Diseases, and Therapeutic Targets.MedComm · 2026Review
- Compensatory scaling of modulatory neural populations in response to motor challenges.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Expression and mechanism of TRPV1 channel in prefrontal cortex after acute hypoxic exercise.BMC sports science, medicine & rehabilitation · 2026Article
- Sarcopenia and sepsis fuel a self-perpetuating cycle of immunometabolism decline.Frontiers in immunology · 2026Review
- A unifying theory of brain signaling and its possible role in acquired chronic disease.Frontiers in neuroscience · 2026Article
- Histone phosphorylation analysis of two main TCM syndromes of chronic fatigue syndrome.Journal of translational medicine · 2025Article
- Excitability of Anterior Horn Cells Following Repetitive Knee Joint Movements at Different Speeds.Cureus · 2025Article
- Anti-central fatigue effects of myelophil in 5-HTergic hyperactivity mice model.BMC complementary medicine and therapies · 2025Article
- Axon initial segment structure and function in health and disease.Physiological reviews · 2025Review
- Transcriptomic alterations in APP/PS1 mice astrocytes lead to early postnatal axon initial segment structural changes.Cellular and molecular life sciences : CMLS · 2024Article
- Sportomics Analyses of the Exercise-Induced Impact on Amino Acid Metabolism and Acute-Phase Protein Kinetics in Female Olympic Athletes.Nutrients · 2024Article
- Exercise-Induced Central Fatigue: Biomarkers and Non-Medicinal Interventions.Aging and disease · 2024Review
- Reduction and recovery of self-sustained muscle activity after fatiguing plantar flexor contractions.European journal of applied physiology · 2024Article
- Interactions between Lateral Hypothalamic Orexin and Dorsal Raphe Circuitry in Energy Balance.Brain sciences · 2024Article
11 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
Motor fatigue induced by physical activity is an everyday experience characterized by a decreased capacity to generate motor force. Factors in both muscles and the central nervous system are involved. The central component of fatigue modulates the ability of motoneurons to activate muscle adequately independently of the muscle physiology. Indirect evidence indicates that central fatigue is caused by serotonin (5-HT), but the cellular mechanisms are unknown. In a slice preparation from the spinal cord of the adult turtle, we found that prolonged stimulation of the raphe-spinal pathway--as during motor exercise--activated 5-HT1A receptors that decreased motoneuronal excitability. Electrophysiological tests combined with pharmacology showed that focal activation of 5-HT1A receptors at the axon initial segment (AIS), but not on other motoneuronal compartments, inhibited the action potential initiation by modulating a Na(+) current. Immunohistochemical staining against 5-HT revealed a high-density innervation of 5-HT terminals on the somatodendritic membrane and a complete absence on the AIS. This observation raised the hypothesis that a 5-HT spillover activates receptors at this latter compartment. We tested it by measuring the level of extracellular 5-HT with cyclic voltammetry and found that prolonged stimulations of the raphe-spinal pathway increased the level of 5-HT to a concentration sufficient to activate 5-HT1A receptors. Together our results demonstrate that prolonged release of 5-HT during motor activity spills over from its release sites to the AIS of motoneurons. Here, activated 5-HT1A receptors inhibit firing and, thereby, muscle contraction. Hence, this is a cellular mechanism for central fatigue.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.