Serotonin affects our perception of fatigue when performing submaximal efforts – but is it all in our heads?

The potent actions of the monoamines serotonin (5HT) and noradrenaline (NA) on the central nervous system (CNS) have long been appreciated and provide the basis for many psychoactive drugs, from Prozac to Ritalin to caffeine. The primary source of these neurotransmitters comes from neurons originating in the brainstem (the raphe nuclei for 5HT and the locus coeruleus and associated nuclei for NA). For over 30 years it has been known that these nuclei not only have ascending projections but also descending projections reaching the spinal cord (Holstege & Kuypers, 1987). These descending axons have multiple targets throughout the spinal cord but their monosynaptic projections to motoneurons are especially strong. Motoneuron dendrites are densely covered with synapses containing either 5HT or NA, which are likely to exert their actions via Gq-coupled receptors (Binder et al. 2020). Probably the strongest effect of these projections is to facilitate persistent inward currents (PICs) mediated by voltage-gated Na+ and Ca2+ channels that are also dendritic. If either of these descending monoaminergic inputs is strongly active, synaptic inputs activate large PICs that amplify inputs generated by motor commands as much as 3to 5-fold. From this amplification and many other results, it is now clear that the descending monoaminergic systems are the primary controllers of the excitability of motoneurons, far outweighing the impact of any of the other descending systems from the cortex or brainstem. Moreover, it has also become apparent that these systems play a fundamental role in normal motor behaviour and probably form the basis for gain control to match the excitability of motoneurons to the wide range of forces needed to implement the diversity of motor behaviours. The pioneers in the study of the anatomy of monoaminergic systems hypothesized that these brainstem nuclei were the link between the ‘emotional’ and ‘movement’ brains, as there are strong inputs to both the raphe and locus coeruleus from the limbic system (Holstege & Kuypers, 1987). This hypothesis makes sense from an evolutionary perspective, where a hunter-gather existence surely required attention and anxiety in response to threats in the environment to be coupled to enhanced capacity for movement. Perhaps this is why exercise ameliorates anxiety – you have escaped the predator and this feels good! Contrast this to the attention and anxiety coupled to watching a TV show – the TV characters have escaped the predator, but you are still sitting in the same spot. Most studies of the effects of the brainstem monoaminergic system on motor control have focused on actions of their descending projections on spinal neurons. In this issue, the paper by Kavanagh et al. (Thorstensen et al. 2020) clearly demonstrates a role for the ascending component of monoaminerigic system during movement, linking the emotional and movement functions of these brainstem nuclei in an unexpected way. The key difference between this work and previous studies is that they focused on submaximal fatigue task (15% of maximum, 30 min duration, not to exhaustion). They found that paroxetine, a selective reuptake blocker for 5HT, significantly increased the subjects’ perception of fatigue in this submaximal task. In addition, they found that paroxetine reduced the length the silent period that accompanies stimulation of the motor cortex. Remarkably, these clear supraspinal effects were not associated with any changes in the execution of the submaximal task. This lack of effect was unlikely to be due to ineffectiveness of paroxetine on the descending serotonergic system. The pre-fatigue contractions showed a clear effect of paroxetine on generation of maximal voluntary contraction (MVC), in that the amplitude of the muscle twitch superimposed on the MVC torque evoked by stimulation at the motor point of the muscle was significantly smaller with paroxetine. This result shows that paroxetine allowed subjects to generate a greater percentage of their true maximum muscle force in the unfatigued state, which is consistent with previous studies showing its impact on motoneuron excitability. Instead, the authors speculate, reasonably, that serotonergic actions at the spinal level may be low in the submaximal state, as a high level motoneuron excitability is not required. Alternatively, they may become reduced during the long duration of the task, as seen in studies of firing patterns of descending serotonergic neurons in the cat (Fornal et al. 2006). Overall, this novel study reveals a paradox in the actions of the serotonergic systems during low intensity, prolonged behaviours. Before fatigue occurs, 5HT availability probably enhances motor output due to its spinal effects. However, when low intensity motor output is prolonged for minutes, the ascending projections of 5HT exacerbate sensations of fatigue. This paradox has a parallel in this group’s previous study (Kavanagh et al. 2019). During shorter motor tasks at high intensity, strong activation of 5HT receptors on the dendrites of motoneurons greatly enhances excitability of motor output, but the resulting build-up of 5HT spills over onto a different type of 5HT receptor on the initial segment of axons to progressively limit motor out. Thus, the serotonergic systems are self-limiting via two very different mechanisms, one descending for short intense outputs (previous studies) and one ascending for prolonged low intensity outputs (this study).