All motor commands from the brain ultimately synapse on the motoneurones in the spinal cord to regulate the timing and amplitude of muscle contractions. The input-output relationship between command signals and motoneuron activation is relatively simple, whereby increases in the firing rate of the command signal cause a greater output response of the motoneuron. However, a complex parallel neuromodulation system is also present, where brainstem pathways release serotonin, otherwise known as 5-hydroxytryptamine (5-HT) in the central nervous system (CNS) to regulate the gain of motoneuron activity. The purpose of this project was to determine if serotonergic effects associated with muscle activation are dependent on the mode of contraction being performed. Healthy young adults were recruited into this study, where motor unit activity was extracted from high density electromyography (HDEMG) collected from the tibialis anterior during isometric dorsiflexion. Three modes of contractions were assessed: a rapid contraction to 30% maximal voluntary contraction (MVC), a slow ramped contraction to 30% MVC, and a sustained fatiguing contraction at 30% MVC that was held to failure. Each participant was tested under normal conditions (placebo) and a condition where 5-HT2A receptors were blocked in the CNS using cyproheptadine. The main finding of the project was that a blockade of 5-HT2A receptors suppressed discharge rate of motor units during a fatiguing isometric 30% MVC contraction of the tibialis anterior muscle. In contrast, there were no drug-related differences when examining the effects of 5-HT2A antagonism for shorter contraction times that were based on rapid contractions or slow ramped contractions to achieve a steady state. It is likely that the prolonged contraction evoked more release of 5-HT into the CNS compared to the shorter duration contractions, and cyproheptadine reduced the ability of 5-HT to excite motoneurons. This project provides a valuable foundation for future research that assessed pharmacological 3 intervention and motor function, as well as research that uses HDEMG to assess motor unit activity for submaximal contractions.