Serotonergic neuromodulation plays a role in enhancing voluntary muscle activation. However, the influence of the potential motoneuron receptor candidate (5-HT2) on the firing rate and activation threshold of motor units (MUs) in humans remains uncertain. This study aimed to investigate the impact of 5-HT2 receptor activity on human MU behavior during gradually increasing contractions of varying intensity. The tibialis anterior muscle's high-density surface electromyography (HDsEMG) was recorded while participants performed ramped isometric dorsiflexions at 10%, 30%, 50%, and 70% of their maximum voluntary contraction (MVC). MU characteristics were extracted from HDsEMG data collected from 11 young adults (including four females) before and after taking either an 8 mg cyproheptadine dose or a placebo. Blocking 5-HT2 receptors led to a decrease in MU discharge rate during steady-state muscle activation, regardless of the contraction intensity (P<0.001; estimated mean difference (Δ)=1.06 pulses/s). Additionally, there was an elevated MU derecruitment threshold (P<0.013, Δ=1.23% MVC), while maximal voluntary contraction force remained unchanged (P=0.652). At 10% MVC (P<0.001, Δ=0.99 Hz) and 30% MVC (P=0.003, Δ=0.75 Hz), there was a reduction in estimates of persistent inward current amplitude, aligning with changes in MU firing behavior attributed to 5-HT2 receptor antagonism. Overall, these findings underscore the role of 5-HT2 receptor activity in regulating discharge rate among groups of spinal motoneurons during voluntary contractions. This study offers evidence of a direct connection between MU discharge properties, persistent inward current activity, and 5-HT2 receptor activity in humans.
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