5‐HT(2) receptor antagonism reduces human motoneuron output to antidromic activation but not to stimulation of corticospinal axons

The intrinsic electrical properties of motoneurons strongly affect motoneuron excitability to fast‐acting excitatory ionotropic inputs. Serotonin (5‐HT) is a neurochemical that alters the intrinsic properties of motoneurons, whereby animal models and in vitro experiments indicate that 5‐HT increases motoneuron excitability by activating 5‐HT(2) receptors on the somato‐dendritic compartment. In the current study, we examined how antagonism of the 5‐HT(2) receptor affects motoneuron excitability in humans. We hypothesised that motoneuron excitability would be reduced. The 5‐HT(2) antagonist cyproheptadine was administered to 10 healthy participants in a double‐blinded, placebo‐controlled, crossover trial. Electrical cervicomedullary stimulation was used to deliver a synchronised excitatory volley to motoneurons to elicit cervicomedullary motor evoked potentials (CMEPs) in the surface electromyography (EMG) signal of the resting biceps brachii. Likewise, electrical peripheral nerve stimulation was used to generate antidromic spikes in motoneurons and cause recurrent discharges, which were recorded with surface EMG as F‐waves in a resting hand muscle. Compared with placebo, we found that 5‐HT(2) antagonism reduced the amplitude and persistence of F‐waves but did not affect CMEP amplitude. 5‐HT(2) antagonism also reduced maximal contraction strength. The reduced recurrent discharge of motoneurons with 5‐HT(2) antagonism suggests that 5‐HT(2) receptors modulate the electrical properties of the initial segment or soma to promote excitability. Conversely, as cyproheptadine did not affect motoneuron excitability to brief synaptic input, but affected maximal contractions requiring sustained input, it seems likely that the 5‐HT(2)‐mediated amplification of synaptic input at motoneuron dendrites is functionally significant only when excitatory input activates persistent inward currents.