Voluntary activation of muscle in humans: does serotonergic neuromodulation matter?

Ionotropic inputs to motoneurones have the capacity to depolarise and hyperpolarise the motoneurone, whereas neuromodulatory inputs control the state of excitability of the motoneurone. Intracellular recordings of motoneurones from in vitro and in situ animal preparations have provided extraordinary insight into the mechanisms that underpin how neuromodulators regulate neuronal excitability. However, far fewer studies have attempted to translate the findings from cellular and molecular studies into a human model. In this review, we focus on the role that serotonin (5‐HT) plays in muscle activation in humans. 5‐HT is a potent regulator of neuronal firing rates, which can influence the force that can be generated by muscles during voluntary contractions. We firstly outline structural and functional characteristics of the serotonergic system, and then describe how motoneurone discharge can be facilitated and suppressed depending on the 5‐HT receptor subtype that is activated. We then provide a narrative on how 5‐HT effects can influence voluntary activation during muscle contractions in humans, and detail how 5‐HT may be a mediator of exercise‐induced fatigue that arises from the central nervous system. figure legend Inputs to neuromodulatory receptors on motoneurones, such as those involved in the serotonergic system, modify the motoneurones’ responsiveness to ionotropic input. The release of serotonin (5‐HT) into the spinal cord is linked to the level of motor activity being performed, where 5‐HT can increase the discharge rate of motoneurones via excitatory 5‐HT receptors on the soma and dendrites. This in turn can lead to increased voluntary muscle activation (VA) and maximal force generation. However, intense release of 5‐HT onto motoneurones may lead to a spillover of 5‐HT into extracellular compartments to activate inhibitory 5‐HT receptors on the axon initial segment. This can cause a reduction in motoneurone discharge rate, thus decreasing VA and maximal force generation. To gain insight into the serotonergic contributions to muscle activation in humans, pharmacological interventions have been employed to enhance the concentration of 5‐HT in the central nervous system or activate selective 5‐HT receptors.