Blockade of 5-HT 2 receptors suppress motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans.

Serotonergic neuromodulation contributes to enhanced voluntary muscle activation. However, it is unknown how the likely motoneurone receptor candidate (5-HT2 ) influences the firing rate, and activation threshold, of motor units (MU) in humans. The purpose of this study was to determine if 5-HT2 receptor activity contributes to human MU behaviour during voluntary ramped contractions of differing intensity. High-density electromyography (HD-EMG) of the tibialis anterior was assessed during ramped isometric dorsiflexions of 10%, 30%, 50% and 70% of maximal voluntary contraction (MVC). MU characteristics were successfully extracted from HD-EMG of 11 young adults (4 female) pre- and post-ingestion of 8 mg cyproheptadine and a placebo. 5-HT2 antagonism caused a reduction in MU discharge rate during steady-state muscle activation that was independent of the level of contraction intensity (p < 0.001, estimated mean difference (∆) = 1.06 pps), as well as an increase in MU derecruitment threshold (p < 0.013, ∆ = 1.23% MVC), without change in force during MVC (p = 0.652). A reduction in estimates of persistent inward current (PIC) amplitude was observed at 10% MVC (p < 0.001, ∆ = 0.99 Hz) and 30% MVC (p = 0.003, ∆ = 0.75 Hz) that aligned with 5-HT changes in MU firing behaviour due to 5-HT2 antagonism. Overall, these findings indicate that 5-HT2 receptor activity has a role in regulating discharge rate in populations of spinal motoneurones when performing voluntary contractions. This study provides evidence of a direct link between MU discharge properties, PIC activity, and 5-HT2 receptor activity in humans. KEY POINTS: Activation of 5-HT receptors on the soma and dendrites of motoneurones regulate their excitability Previous work using chlorpromazine and cyproheptadine have demonstrated that the 5-HT2 receptor regulates motoneurone activity in humans with chronic spinal cord injury and non-injured controls It is unknown how the 5-HT2 receptor directly influences motor unit discharge and motor unit recruitment in larger populations of human motoneurones during voluntary contractions of differing intensity Despite the absence of change in force during maximal voluntary dorsiflexions, 5-HT2 receptor antagonism caused a reduction in motor unit discharge rate during submaximal steady-state muscle contraction, as well as an increase in motor unit derecruitment threshold, irrespective of the submaximal contraction intensity Reductions in estimates of persistent inward currents (PIC) after 5-HT2 receptor antagonism support the viewpoint that the 5-HT2 receptor plays a critical role in regulating motor activity, where a PIC-based mechanism is involved in regulating the excitability of human motoneurones Abstract figure legend High density surface electromyography (HDsEMG) was sampled from tibialis anterior during voluntary submaximal dorsiflexion contractions. Motor units extracted from HDsEMG were tracked within each contraction intensity from pre to post ingestion of a placebo and cyproheptadine, a 5-HT2 receptor antagonist. After the ingestion of cyproheptadine there was a reduction in motor unit discharge rate, a reduction in estimates of persistent inward currents (delta F), and an increase in derecruitment threshold. This article is protected by copyright. All rights reserved.