Serotonergic and noradrenergic contributions to motor cortical and spinal motoneuronal excitability in humans

Animal models indicate that motor behaviour is shaped by monoamine neuromodulators released diffusely throughout the brain and spinal cord. As an alternative to conducting a single study to explore the effects of neuromodulators on the human motor system, we have identified and collated human experiments investigating motor effects of well-characterised drugs that act on serotonergic and noradrenergic networks. In doing so, we present strong neuropharmacology evidence that human motor pathways are affected by neuromodulators across both healthy and clinical populations, insight that cannot be determined from a single reductionist experiment. We have focused our review on the effects that monoaminergic drugs have on muscle responses to non-invasive stimulation of the motor cortex and peripheral nerves, and other closely related tests of motoneuron excitability, and discuss how these measurement techniques elucidate the effects of neuromodulators at motor cortical and spinal motoneuronal levels. Although there is some heterogeneity in study methods, we find drugs acting to enhance extracellular concentrations of serotonin tend to reduce the excitability of the human motor cortex, and enhanced extracellular concentrations of noradrenaline increases motor cortical excitability by enhancing intracortical facilitation and reducing inhibition. Both monoamines tend to enhance the excitability of spinal motoneurons. Overall, this review details the importance of neuromodulators for the output of human motor pathways and suggests that commonly prescribed monoaminergic drugs target the motor system in addition to their typical psychiatric/neurological indications.