Serotonergic Modulation of Motoneuronal Excitability and Its Impact on Muscle Force Generation: A Computational Study

Abstract

This study investigated the modulatory effects of serotonin (5-HT) on motor neuron excitability and muscle force generation using a computational model. The impact of 5-HT receptor activation was evaluated across a range of stimulation frequencies. Physiological concentrations of 5-HT significantly enhanced motor neuron excitability at 40 Hz and 100 Hz (p < 0.0001), consistent with the excitatory role of 5-HT₂A receptor activation. In contrast, supraphysiological levels of 5-HT reduced excitability, likely due to overactivation of inhibitory 5-HT₁A receptors, which induce neuronal hyperpolarization. Muscle force output was positively correlated with motor neuron activity. At 10 Hz, physiological 5-HT release had no significant effect on force generation, suggesting minimal influence at low stimulation frequencies. However, elevated 5-HT levels shortened contraction duration, indicating the onset of muscle fatigue (p < 0.0001). At higher frequencies, physiological 5-HT supported sustained muscle contractions, whereas excessive 5-HT impaired contraction maintenance, promoting fatigue (p < 0.0001). These results are consistent with experimental observations and support the validity of the model as a reliable tool for investigating serotonergic modulation of neuromuscular function. The model provides mechanistic insights into fatigue development and may inform therapeutic strategies targeting serotonergic pathways to improve muscle performance and recovery. Future studies should explore interactions with other neurotransmitter systems to further elucidate their contributions to motor control and fatigue resistance.