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

Abstract

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) 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). 5‐HT2 antagonism reduced maximal torque (p < 0.001), and compared to placebo, reduced 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.

Antagonism of 5‐HT2 receptors attenuates self‐sustained firing of human motor units

“…Although the effects of antihistamines have not been assessed in human MU investigations, a potent antihistaminergic and antimuscarinic drug (promethazine) generates almost no effects on corticospinal excitability or motoneurone excitability across a wide range of muscle contractions in humans (Dempsey & Kavanagh, 2021, 2023). Cyproheptadine has repeatedly been used for the antagonism of the serotonergic system both by our lab group (Goodlich et al., 2022, 2023a; Henderson et al., 2024; Thorstensen et al., 2021, 2022) and other groups (D'Amico et al., 2013; Murray et al., 2010, 2011; Wei et al., 2014). Although these studies could not separate antihistaminergic effects from antiserotonergic effects, almost every investigation highlighted the close alignment between their human findings and animal/cellular preparations that have used targeted 5‐HT drugs.…”

“…Thus, PICs may have been required to shift from a relatively inactive state to a relatively more active state after depolarisation commenced from the addition of excitatory synaptic input. Converging lines of evidence suggest that excitatory synaptic input is needed to observe serotonergic effects in human spinal motoneurone excitability (Henderson et al., 2024; Thorstensen et al., 2022), so it is possible that the effects of serotonergic neuromodulation, and in particular self‐sustained firing of motoneurones, will differ depending on the initial state of the motor system.…”