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

Figure 1. Serotonergic activity modulates cortical and spinal motoneurone activity A, serotonin synthesis in the mammalian CNS occurs in the raphe complex of the brainstem. Rostral raphe nuclei ascend primarily to the forebrain to innervate virtually all regions. Caudal raphe nuclei project mainly to the cerebellum and spinal cord, where the monosynaptic raphe–spinal pathway releases 5‐HT on the soma and dendrites of spinal motoneurones. Ionotropic inputs from descending motor cortical pathways, peripheral afferents, or spinal interneurons, have the capacity to depolarise and hyperpolarise the motoneurone. However, activation of 5‐HT receptors, predominantly in the 5‐HT1 and 5‐HT2 families, regulates the state of excitability of the motoneurone via intracellular signalling pathways to modify the motoneurone's responsiveness to ionotropic input. B, intracellular recordings from motoneurones in an adult turtle spinal cord preparation (black). The number of action potentials evoked by depolarizing current pulses injected in the soma is increased following 1 s of 40 Hz electrical stimulation of the dorsolateral funiculus (red), which contains descending serotonergic fibres of the raphe–spinal…

Figure 2. Elbow flexion MVC torque after ingestion of paroxetine or cyproheptadine A, the SSRI paroxetine (Parox) exerts small, but significant, increases in torque during brief unfatigued MVCs (paired Student's t‐test, P = 0.046). Given that voluntary activation of biceps is high in healthy individuals (e.g. 97–99%), a ceiling effect exists whereby only small increases in voluntary activation and elbow flexion torque are possible. B, competitive antagonism of the 5‐HT2 receptor via cyproheptadine (Cypro) causes significant reductions in the ability to generate elbow flexion torque during brief unfatigued MVCs (paired t‐test, P = 0.003). Data are sourced from a combination of studies from the host laboratory using healthy adults aged 20–30 year (Henderson et al., 2022; Kavanagh et al., 2019; Thorstensen et al., 2020; Thorstensen et al., 2021).

Figure 3. The effect of enhanced availability of 5‐HT on maximal and submaximal fatiguing isometric contractions Paroxetine (Parox) was used to enhance 5‐HT concentrations by reuptake inhibition. Motor nerve stimulation was used to assess voluntary activation of the elbow flexors. A, time‐to‐task failure was assessed for four sustained maximal elbow flexions, where each contraction was maintained until force declined to 60% MVC. Grey bars indicate a fatiguing contraction has occurred. A rest period of 40 s occurred between maximal contractions. B, each fatiguing contraction was followed 3 s later by a resting twitch, and then 3 s later by a brief maximal contraction with superimposed twitch, where voluntary activation was calculated as: [1 − (superimposed twitch/resting twitch)] × 100. Enhanced 5‐HT concentration caused a significantly greater fatigue‐related reduction in time‐to‐task failure (P = 0.038) and voluntary activation (P = 0.048). C, elbow flexion torque has also been assessed during a sustained 15% MVC, where the contraction was held for 30 min and fatigue responses continued to be monitored for 10 min of recovery. D, superimposed and resting twitches were obtained periodically…