Human motoneurone excitability is depressed by activation of serotonin 1A receptors with buspirone

Abstract

Intense serotonergic drive in the turtle spinal cord results in serotonin spillover to the axon initial segment of the motoneurones where it activates serotonin 1A (5-HT ) receptors and inhibits generation of action potentials. We examined whether activation of 5-HT receptors decreases motoneurone excitability in humans by determining the effects of a 5-HT receptor partial agonist, buspirone, on F waves and cervicomedullary motor evoked potentials (CMEPs). In a placebo-controlled double-blind study, 10 participants were tested on two occasions where either placebo or 20 mg of buspirone was administered orally. The ulnar nerve was stimulated supramaximally to evoke F waves in abductor digiti minimi (ADM). CMEPs and the maximal M wave were elicited in biceps brachii by cervicomedullary stimulation and brachial plexus stimulation, respectively. Following buspirone intake, F-wave area and persistence, as well as CMEP area, were significantly decreased. The mean post-pill difference in normalized F-wave areas and persistence between buspirone and placebo days was -27% (-42, -12; 95% confidence interval) and -9% (-16, -2), respectively. The mean post-pill difference in normalized CMEP area between buspirone and placebo days showed greater variation and was -31% (-60, -2). In conclusion, buspirone reduces motoneurone excitability in humans probably via activation of 5-HT receptors at the axon initial segment. This has implications for motor output during high drive to the motoneurones when serotonin may spill over to these inhibitory receptors and consequently inhibit motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise.

Enhanced availability of serotonin increases activation of unfatigued muscle but exacerbates central fatigue during prolonged sustained contractions

“…Ingestion of the 5‐HT1 A agonist, buspirone, induces clear reductions in motoneurone excitability (D'Amico et al . ), which limits the capacity to perform prolonged bouts of exercise (Marvin et al . ).…”

“…Although 5-HT mechanisms that reduce motoneurone excitability have been identified for the turtle spinal cord, the inhibitory effect that 5-HT 1A receptors have on motor function has also been confirmed in humans. Ingestion of the 5-HT1 A agonist, buspirone, induces clear reductions in motoneurone excitability (D'Amico et al 2017), which limits the capacity to perform prolonged bouts of exercise (Marvin et al 1997). It should be noted, however, that exogenous activation of the 5-HT 1A receptor may cause different responses to endogenously released 5-HT.…”

“…) and suppresses spinal motoneurone excitability (D'Amico et al . ). Therefore, a reduction in motoneurone firing due to inhibitory actions of 5‐HT provides a spinal mechanism by which higher concentrations of 5‐HT may contribute to declines in motor performance during fatigue‐inducing exercise.…”

“…Activating 5-HT 1A receptors on the axon initial segment causes inwardly rectifying K + conductance via GIRK (K3) channels to create a state of tonic hyperpolarization, and inhibits Na + channels that are responsible for the genesis of action potentials (Williams et al 1988;Bayliss et al 1997;Cotel et al 2013;Petersen et al 2015). This mechanism also appears relevant to humans, as ingestion of a 5-HT 1A receptor agonist reduces the capacity to perform prolonged bouts of exercise (Marvin et al 1997) and suppresses spinal motoneurone excitability (D'Amico et al 2017). Therefore, a reduction in motoneurone firing due to inhibitory actions of 5-HT provides a spinal mechanism by which higher concentrations of 5-HT may contribute to declines in motor performance during fatigue-inducing exercise.…”

Corticospinal excitability during fatiguing whole body exercise

“…It was therefore concluded that fatiguing cycling exercise results in an inhibition, or disfacilitation, of the spinal motoneurons. Potential mechanisms for decreased excitability of the motoneuron pool resulting from fatiguing exercise include alterations in motoneuronal membrane potential (e.g., increased after-hyperpolarization (Matthews, 1999)), activation of extrasynaptic serotonin 1A receptors (D’Amico et al, 2017), and insufficient release, or depletion, of neurotransmitters (e.g., acetylcholine) resulting from repetitive activation.…”