Blockade of 5‐HT<sub>2</sub> receptors suppresses motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans

Goodlich, Benjamin I; Vecchio, Alessandro Del; Horan, Sean; Kavanagh, Justin J.

doi:10.1113/jp284164

Cited by 24 publications

(26 citation statements)

References 61 publications

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“…Such changes could be brought about by a change in the balance of synaptic inputs driving the motoneurone pool. Consistent with this idea, 5-HT2 antagonism was found to reduce estimates of PICs during low intensity dorsiflexion contractions (Goodlich et al, 2023). This same effect may be present in the current study as 5-HT2 antagonism also reduced maximal elbow flexion torque.…”

Section: -Ht2 Antagonism Exerts Effects On Spinal Motoneurones Only W...supporting

confidence: 90%

“…Since 5-HT2 antagonism can increase measures of motor cortical inhibition (Thorstensen et al, 2021) and reduce estimates of PICs at motoneurones (D'Amico et al, 2013;Goodlich et al, 2023), we hypothesised that 5-HT2 receptor antagonism would increase intracortical inhibition, and reduce motoneurone excitability during voluntary contractions.…”

Section: Introductionmentioning

confidence: 99%

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Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT₂receptors in humans

Henderson

Taylor

Thorstensen

et al. 2023

Preprint

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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.

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Section: -Ht2 Antagonism Exerts Effects On Spinal Motoneurones Only W...supporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT₂receptors in humans

Henderson

Taylor

Thorstensen

et al. 2023

Preprint

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“…We observed that onset-offset hysteresis (i.e., ΔF) is greater at higher contraction levels, which suggests that the contribution of PICs to self-sustained motoneuron discharge increases as a function of contraction force. These results are consistent with prior reports in the tibialis anterior and gastrocnemius medialis muscles (Orssatto et al ., 2021; Goodlich et al ., 2023), but contrast reports of no differences in discharge rate hysteresis with increased contraction levels in tibialis anterior and soleus (Kim et al ., 2020; Afsharipour et al ., 2020). Though the reason for these conflicting findings is difficult to discern, methodological factors are plausible contributors.…”

Section: Discussionmentioning

confidence: 99%

“…However, when examined across different contraction levels, findings regarding ΔF remain inconclusive. ΔF has been shown to either increase (Orssatto et al ., 2021; Goodlich et al ., 2023) or remain constant (Kim et al ., 2020; Afsharipour et al ., 2020) with increased voluntary drive. Although monoaminergic inputs likely vary between motor pools (Hounsgaard et al ., 1988; Wilson et al ., 2015) and could conceivably explain these varied findings, inconsistencies are still reported when examining the same muscle (Kim et al ., 2020; Orssatto et al ., 2021).…”

Section: Introductionmentioning

confidence: 99%

Human motor unit discharge patterns reveal differences in neuromodulatory and inhibitory drive to motoneurons across contraction levels

Škarabot,

Beauchamp,

Pearcey

2023

Preprint

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Transformation of motor commands via a motor unit (MU) into mechanical actions of muscle fibres is a non-linear function influenced by ionotropic excitatory/inhibitory and neuromodulatory inputs. Neuromodulatory inputs facilitate dendritic persistent inward currents on motoneurons, which introduce non-linearities in MU discharge patterns allowing estimation of the structure of motor commands. We investigated the relative contribution of neuromodulation and the pattern of inhibition to human MU discharge patterns with increasing contraction force. In Experiment 1, we identified MU discharges in tibialis anterior, and vastus lateralis and medialis during isometric triangular dorsiflexion and knee extension contractions, respectively, up to 70% of maximal voluntary force (MVF). We quantified the onset-offset hysteresis (ΔF) and performed quasi-geometric analyses of MU discharge patterns to quantify the magnitude of non-linearity, and slopes of MU discharge patterns during the acceleration and rate attenuation regions. We show that ΔF increased, whereas discharge patterns became more linear and had lower slopes at greater contraction forces. Experiment 2 required participants to dorsiflex up to 70% MVF with either matched duration or rate of force increase to determine if these factors were confounding the modulation in MU discharge patterns across contraction forces. Though ΔF and the magnitude of non-linearity were influenced by contraction duration, the relative changes in these variables across contraction forces were similar to Experiment 1. The results suggest that neuromodulatory input and patterns of inhibition are uniquely shaped to support force increases across a large proportion of the motor pool's recruitment range in three human lower limb muscles.

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“…This is a big challenge because direct measures of, for example, serotonergic input onto motor neurones are properties of voltage-gated channels are invasive and not feasible yet in humans. Thus, pharmacological or exercise strategies for manipulation of monoamines input onto motor neurones -such as blockade of 5-HT 2 receptors to attenuate F (Goodlich et al, 2023) or varying contraction intensities (Orssatto, Mackay et al, 2021, 2023 and the use of remote contractions to increase F (Orssatto, Fernandes et al, 2022) -could be further explored to understand the role of serotonin on age-related reductions in PICs.…”

Section: What Is Not Known About Pics With Respect To Ageing and Exer...mentioning

confidence: 99%

Ageing reduces persistent inward current contribution to motor neurone firing: Potential mechanisms and the role of exercise

Orssatto,

Blazevich,

Trajano

2023

The Journal of Physiology

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Nervous system deterioration is a primary driver of age‐related motor impairment. The motor neurones, which act as the interface between the central nervous system and the muscles, play a crucial role in amplifying excitatory synaptic input to produce the desired motor neuronal firing output. For this, they utilise their ability to generate persistent (long‐lasting) depolarising currents that increase cell excitability, and both amplify and prolong the output activity of motor neurones for a given synaptic input. Modulation of these persistent inward currents (PICs) contributes to the motor neurones’ capacities to attain the required firing frequencies and rapidly modulate them to competently complete most tasks. Thus, PICs are crucial for adequate movement generation. Impairments in intrinsic motor neurone properties can impact motor unit firing capacity, with convincing evidence indicating that the PIC contribution to motor neurone firing is reduced in older adults. Indeed, this could be an important mechanism underpinning the age‐related reductions in strength and physical function. Furthermore, resistance training has emerged as a promising intervention to counteract age‐associated PIC impairments, with changes in PICs being correlated with improvements in muscular strength and physical function after training. In this review, we present the current knowledge of the PIC magnitude decline during ageing and discuss whether reduced serotonergic and noradrenergic input onto the motor neurones, voltage‐gated calcium channel dysfunction or inhibitory input impairments are candidates that: (i) explain age‐related reductions in the PIC contribution to motor neurone firing and (ii) underpin the enhanced PIC contribution to motor neurone firing following resistance training in older adults. image

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Blockade of 5‐HT₂ receptors suppresses motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans

Abstract: support-information-section).

Cited by 24 publications

References 61 publications

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT₂receptors in humans

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT₂receptors in humans

Human motor unit discharge patterns reveal differences in neuromodulatory and inhibitory drive to motoneurons across contraction levels

Ageing reduces persistent inward current contribution to motor neurone firing: Potential mechanisms and the role of exercise

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Blockade of 5‐HT2 receptors suppresses motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans

Abstract: support-information-section).

Cited by 24 publications

References 61 publications

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT2receptors in humans

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT2receptors in humans

Human motor unit discharge patterns reveal differences in neuromodulatory and inhibitory drive to motoneurons across contraction levels

Ageing reduces persistent inward current contribution to motor neurone firing: Potential mechanisms and the role of exercise

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Blockade of 5‐HT₂ receptors suppresses motor unit firing and estimates of persistent inward currents during voluntary muscle contraction in humans

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT₂receptors in humans

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT₂receptors in humans