The role of serotonin in human corticospinal-motoneuronal function

Abstract

Serotonin (5-HT) has strong effects on motor function; whereby converging lines of evidence indicate that 5-HT modulates spinal motoneuron excitability to regulate motor output. In the nervous system, 5-HT neurons form monosynaptic connections with motoneurons, and animal studies indicate that 5-HT release onto motoneurons varies in proportion to the intensity of motor activity. In this regard, strong motor activity causes large 5-HT release that activates excitatory somato-dendritic 5-HT2 receptors, which tends to facilitate motoneuron gain. Yet, 5-HT release to motoneurons also contribute to central fatigue via an inhibitory mechanism. Excessive 5-HT release during fatiguing motor behaviours can reduce motoneuron excitability by activating inhibitory 5-HT receptors located at the motoneuronal axon initial segment. To date, there are limited human studies that have examined serotonergic effects on motor function. Therefore, the purpose of this thesis was to explore how human corticospinal-motoneuronal function is modulated by 5-HT activity and to translate serotonergic mechanisms from animal models and in vitro studies to human neurophysiology experiments. Using double-blind, placebo-controlled, crossover designs, all studies in this thesis assessed the effects of serotonergic drugs on isometric muscle contractions and muscle responses to stimulation of the motor cortex, cervicomedullary junction or peripheral nerves in healthy participants. In Study 1, to examine the contribution of 5-HT to submaximal fatigue, the selective 5-HT reuptake inhibitor (SSRI) paroxetine was administered to increase 5-HT availability in synapses. After paroxetine administration, Study 1 assessed the ability of participants to generate maximal elbow flexions that were intermittently performed during a prolonged low-intensity elbow flexion, and it was found that paroxetine did not affect maximal contractions or voluntary activation (i.e., measures of central fatigue), but increased fatigue perceptions and shortened the transcranial magnetic stimulation (TMS) silent period recorded in the fatigued biceps brachii. For Study 2 and 3, the 5-HT2 antagonist cyproheptadine was administered to attenuate the facilitatory effects of 5-HT at motoneurons. Study 2 assessed how 5-HT2 antagonism affected muscle responses to TMS of the motor cortex, whereby the strength of elbow flexion was fixed and the intensity of TMS was manipulated, or the strength of elbow flexion was manipulated and the intensity of TMS was fixed. For the fixed-intensity elbow flexions, 5-HT2 antagonism reduced the amplitude of biceps motor evoked potentials (MEPs) across a spectrum of TMS intensities, but reductions in MEP amplitude with cyproheptadine were largest with high-intensity TMS. In the same study, during elbow flexions of different strengths, it was found that 5-HT2 antagonism reduced maximal contraction torque and lengthened the TMS silent period only during maximal effort contractions. Lastly, Study 3 assessed the effects of 5-HT2 antagonism on biceps cervicomedullary motor evoked potentials (CMEPs) and F-waves in the abductor digiti minimi (ADM). In Study 3, cyproheptadine reduced the amplitude and persistence of ADM F-waves but did not affect the amplitude of biceps CMEPs from corticospinal axon stimulation. Study 3 also found that 5-HT2 antagonism reduced maximal elbow flexion strength, which replicated findings from Study 2. Overall, this thesis presents novel human evidence that serotonergic effects at motoneurons depend on the intensity of motor activity. In addition to 5-HT effects at motoneurons, some findings indicate that 5-HT modulates motor cortical function and/or the activity of other supraspinal networks indirectly involved in voluntary movement.