Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT2 receptors in humans

Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT2 receptors. However, the effects of these receptors on cortical and motoneurone excitability during voluntary contractions have not been explored in humans. Therefore, the purpose of this study was to investigate how 5-HT2 antagonism affects corticospinal and motoneuronal excitability with and without descending drive to motoneurones. Twelve individuals (aged 24 {+/-} 4 years old) participated in a double-blind, placebo-controlled, crossover study, whereby the 5-HT2 antagonist cyproheptadine was administered. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex to produce motor evoked potentials (MEPs) and electrical stimulation at the cervicomedullary junction was used to generate cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii at rest and during a range of submaximal elbow flexions. Evoked potentials were also obtained after a conditioning TMS pulse to produce conditioned MEPs and CMEPs (100 ms inter-stimulus interval). Compared to placebo, 5-HT2 antagonism reduced maximal elbow flexion torque (p = 0.004), unconditioned MEP amplitude at rest (p = 0.003), conditioned MEP amplitude at rest (p = 0.033), and conditioned MEP amplitude during contractions (p = 0.020). 5-HT2 antagonism also increased unconditioned CMEP amplitude during voluntary contractions (p = 0.041) but not at rest. Although 5-HT2 antagonism increased long-interval intracortical inhibition, net corticospinal excitability was unaffected during voluntary contractions. Given that spinal motoneurone excitability was only affected when descending drive to motoneurones was present, the current study indicates that excitatory drive is necessary for 5-HT2 receptors to regulate motoneurone excitability but not intracortical circuits. Significance statementCellular and animal preparations have revealed that somatodendritic 5-HT2 receptors on motoneurones can modulate motoneurone excitability. However, it is mostly unknown how 5-HT2 receptors modulate motor cortical and motoneurone activity to generate muscle contractions in humans. Here we show that antagonism of 5-HT2 receptors reduced muscle responses to motor cortical stimulation only when the muscle was at rest, or when voluntary motor activity was interrupted by a conditioning TMS stimulus. In contrast, antagonism of 5-HT2 receptors increased the muscle response to cervicomedullary electrical stimulation, but only when descending drive to motoneurones was present. These findings not only suggest that 5-HT2 receptors modulate intracortical and motoneurone activity, but sustained synaptic excitation of motoneurones is required for serotonergic mechanisms to modulate motoneurones.