5.9 Serotonin, Noradrenaline, and Acetylcholine: The Other Modulatory Systems

Executive summary. Dopamine dominates popular discussion, but it does not act alone and it does not explain most of what athletes actually experience. Noradrenaline from the locus coeruleus sets arousal and controls the trade-off between persisting with the current task and switching to something else. Serotonin from the raphe nuclei is implicated in mood, in aggression regulation, and in a well-supported computational account, in patience — the willingness to tolerate delay before reward. Acetylcholine from the basal forebrain raises signal-to-noise and gates whether a moment is eligible for lasting change. Together these three explain readiness, tolerance of discomfort, and why distracted practice does not stick. This article covers each system, the real shape of the arousal-performance relationship, and how to manipulate state in a warm-up.

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Key takeaways

1. Noradrenaline is best described as a gain control. It does not add information; it changes how strongly existing signals are treated, and it biases between exploiting the current task and exploring alternatives.
2. The arousal-performance inverted U is not one curve. Its peak shifts left as task complexity rises, which is why maximal-force and decision-heavy tasks need different pre-task states.
3. Serotonin has a strong claim to encoding patience and time horizon. Low serotonergic function is associated with steeper discounting of delayed rewards.
4. Acetylcholine gates plasticity. Attention is not merely psychological; it physically determines which circuits are eligible to change.
5. All three systems are degraded by sleep loss, and the locus coeruleus in particular is a documented site of vulnerability to chronic sleep disruption.
6. A warm-up is an arousal-setting tool, not only a tissue-temperature tool. Its endpoint should be chosen from the task, not from habit.

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Beginner section: Readiness, patience, and focus

Three everyday training experiences map cleanly onto three chemical systems.

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The first is readiness. Some days you feel switched on from the first warm-up set; other days you feel like you are operating through fog. That axis is largely noradrenaline, produced by a small cluster of cells in the brainstem called the locus coeruleus that projects almost everywhere in the brain. When it fires more, everything gets treated as more urgent and more important.

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The second is patience. Training is a long sequence of costs paid now for rewards that arrive much later, and how tolerable that feels varies. Serotonin, produced by the raphe nuclei, is heavily implicated in how willing you are to wait — and low serotonergic function is associated with wanting the smaller reward sooner.

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The third is focus. Acetylcholine does two entirely separate jobs in your body. At the junction between nerve and muscle it is what actually makes a muscle fibre contract. In the brain it sharpens whatever you are attending to and, crucially, opens the window in which learning can occur.

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The third one has the most surprising practical consequence, so it is worth stating directly: Practice you did not attend to does not consolidate well. This is not a motivational slogan. Cholinergic signalling gates plasticity, so a set performed while scrolling on your phone between reps is physically less eligible to produce durable change than the same set performed with attention on it.

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The beginner-level summary is therefore: Manage arousal to fit the task, expect patience to be a variable rather than a trait, and protect attention for the parts of the session that you actually need to get better at.

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Advanced section: Three computations, and the real shape of the arousal curve

Noradrenaline: Gain, and the exploit-explore trade-off

The locus coeruleus contains only a few thousand neurons per side in humans, yet it supplies most of the noradrenaline in the forebrain (Berridge & Waterhouse, 2003). Its projections are extraordinarily divergent, which makes it structurally suited to setting a global parameter rather than carrying specific content.

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Aston-Jones and Cohen’s adaptive gain theory is the most influential functional account. They distinguish two modes. In phasic mode, locus coeruleus neurons have moderate baseline firing and produce crisp bursts to task-relevant stimuli; this state supports focused exploitation of the current task and is associated with good performance. In tonic mode, baseline firing is high and phasic responses are blunted; this state promotes disengagement and exploration of alternatives, and is associated with distractibility and restlessness (Aston-Jones & Cohen, 2005).

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Read as a training variable, this reframes over-arousal usefully. An athlete who is highly activated but performing badly at a complex task is not simply nervous. They may be in a high-tonic state in which nothing gets prioritised because everything is amplified.

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The Yerkes-Dodson relationship is over a century old and is frequently cited as a single curve, which loses its most useful feature. The original work already indicated that the optimum shifts with task difficulty (Yerkes & Dodson, 1908). For a maximal deadlift — simple, brief, high-force — very high arousal is close to optimal. For reading a defence and selecting a response, the optimum sits considerably lower, and an athlete driven to maximal activation will perform worse than one who was left alone.

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Serotonin: Patience, mood, and the cost of waiting

Serotonergic neurons are concentrated in the raphe nuclei and project widely to cortex, striatum, hippocampus and hypothalamus. Fourteen or more receptor subtypes are recognised, which is a large part of why simple statements about serotonin so often fail.

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The computational account with the best support relates serotonin to temporal discounting and patience. Tryptophan depletion studies, which acutely lower brain serotonin synthesis, tend to increase preference for smaller immediate rewards over larger delayed ones and to increase impulsive responding (Crockett et al., 2009). Conversely, serotonergic manipulations that raise signalling tend to increase willingness to wait (Miyazaki et al., 2012). Cools, Nakamura and Daw’s synthesis frames dopamine and serotonin as complementary: Dopamine biasing towards action and reward pursuit, serotonin towards patience and tolerance of aversive delay (Cools et al., 2011).

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This is directly relevant to endurance and to adherence. Both are, structurally, patience problems. It also gives a mechanistic reading of a familiar phenomenon: When sleep-deprived and under-fed, athletes make characteristically short-horizon decisions — abandoning pacing plans, skipping the parts of a session with delayed payoff — and this is better understood as a shifted time horizon than as weak character.

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• What is well supported. Serotonergic function influences impulsivity, temporal discounting and mood; acute tryptophan depletion reliably shifts these measures; serotonergic drugs have well-documented clinical effects.
• What is not well supported. That depression is caused by a simple serotonin deficiency. That framing has been substantially revised, and umbrella reviews have found the evidence for a straightforward serotonin-deficiency model to be weak (Moncrieff et al., 2023). Antidepressants can be effective without the deficiency story being correct.
• What follows for training. Very little pharmacologically, and quite a lot behaviourally. Patience is state-dependent, so protect the states — sleep, energy availability, stress load — that support it rather than expecting it to be constant.

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Acetylcholine: Gating what gets learned

Central cholinergic projections arise principally from the basal forebrain, including the nucleus basalis of Meynert, and from brainstem nuclei. Their cortical effect is often summarised as increasing signal-to-noise: Amplifying the response to attended, behaviourally relevant input while suppressing background activity and reducing the spread of activity between cortical columns (Hasselmo & Sarter, 2011).

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The plasticity-gating role is demonstrated experimentally in a striking way. Pairing a tone with stimulation of the nucleus basalis produces reorganisation of auditory cortex around that tone, in animals that had no task to perform and no reward involved (Kilgard & Merzenich, 1998). The cholinergic signal was sufficient to make the cortex treat that input as worth reorganising around. Sarter and colleagues developed the broader account of cortical cholinergic input as implementing attentional effort (Sarter et al., 2006).

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For coaching, this converts “pay attention” from a moral instruction into a mechanistic one. If a set is performed with attention elsewhere, the neuromodulatory conditions for durable change are less favourable, regardless of how many repetitions were completed. It also gives a reason to prefer fewer, better-attended repetitions when learning a new movement, and to accept lower attention on well-automated work.

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How the three interact, and what sleep loss does to all of them

These systems are not independent. Locus coeruleus and raphe activity both vary strongly across the sleep-wake cycle, falling to near-silence in rapid eye movement sleep for noradrenergic neurons (Berridge & Waterhouse, 2003). Cholinergic activity, by contrast, is high in both waking and REM sleep, which is part of why REM is implicated in consolidation.

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Sleep restriction affects all three. Beyond the well-known effects on alertness, there is evidence that chronic sleep disruption is associated with damage to locus coeruleus neurons in animal models (Zhang et al., 2014), which is a more serious claim than transient tiredness and one reason to treat chronic sleep debt as a genuine risk rather than an inconvenience.

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The practical synthesis is that state is not a single dial. An athlete can be highly aroused and unfocused, or calm and sharply attentive, or alert and impatient. Diagnosing which of these is present tells you what to change: Arousal problems respond to warm-up and environment, focus problems to task design and distraction removal, patience problems mostly to sleep, food and load management.

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Practical section: Setting state on purpose

The most useful application of this chapter is a warm-up that ends in the right state rather than simply ending.

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• For maximal strength attempts: Drive arousal high. Longer, more intense priming, higher-intensity music if it helps you, aggressive breathing, and short rest before the attempt. High arousal costs little on a simple task.
• For technical skill under pressure: Deliberately cap arousal. Longer, slower breathing, quieter environment, more rehearsal at submaximal intensity, and resist the urge to add stimulation.
• For learning a new movement: Prioritise attention over volume. Fewer sets, no phone, external focus cue, immediate feedback. This is the cholinergic case, and volume without attention is largely wasted.
• For long, uncomfortable sessions: Treat patience as the limiting resource. Pre-commit to the plan in writing, break the session into stages with defined endpoints, and do not make pacing decisions while deep in fatigue.
• For competition day: Know which curve your event sits on. A thrower and a point guard should not arrive in the same state, and generic hype serves the first much better than the second.

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Two general points. First, arousal is easier to raise than to lower, so err on the low side and build up rather than over-activating and trying to come back down. Second, none of this substitutes for sleep. Every system in this article degrades with sleep restriction, and no warm-up protocol compensates for it.

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Sport applications

• Throwing and maximal lifting. High arousal is close to optimal. Aggressive activation strategies are appropriate here and nowhere else by default.
• Basketball, football and rugby playmaking. Decision-heavy roles peak at lower arousal. Over-hyping a decision-maker degrades exactly the quality you need.
• Archery, shooting and golf. Very low optimal arousal, high cholinergic focus demand. Downregulation skills are the primary psychological training target.
• Endurance racing. A patience problem in disguise. Pre-committed pacing rules protect against the shortened time horizon that accompanies fatigue.
• Combat sports. Requires holding moderate arousal with high attentional selectivity, which is why fighters who arrive over-activated gas early and read poorly.

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Common mistakes

• Assuming more arousal is always better. The optimum shifts left as complexity rises. Complex tasks are harmed by activation that helps simple ones.
• Treating focus as optional during skill work. Cholinergic gating means unattended practice is physically less eligible to consolidate.
• Believing the serotonin-deficiency account of low mood. That model has been substantially revised. Do not build training or supplement decisions on it.
• Making pacing decisions while exhausted. Time horizon shortens with fatigue. Decide in advance, in writing.
• Using the same warm-up for every session. A warm-up should end in a state chosen for the task, and tasks differ.
• Expecting a protocol to replace sleep. All three systems degrade with sleep restriction, and none of the tools here compensate.

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Coaching cues

• Choose the arousal you want before you choose the warm-up.
• Raise arousal for force, cap it for decisions.
• Phone away for anything you are trying to learn.
• Fewer, better-attended reps beat more, unattended reps when learning.
• Write the pacing plan before the session, not during it.
• If patience is gone, look at sleep and food before looking at willpower.

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FAQs

What is the optimal arousal level for training?

There is not one. The performance-arousal relationship is an inverted U whose peak moves depending on how complex the task is. Brief, simple, high-force tasks tolerate and often benefit from very high arousal. Complex tasks involving decisions, fine control or reading an opponent peak at noticeably lower arousal. Choosing a single pre-session state for all training is one of the more common avoidable errors.

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Does low serotonin cause depression?

The simple deficiency model is not well supported and has been substantially revised, including by umbrella reviews of the serotonin literature. Serotonergic function clearly influences mood, impulsivity and patience, and serotonergic medications have documented clinical effects, but neither of those establishes that depression is caused by a serotonin shortage. Depression is a clinical condition with multiple contributors and should be assessed by a professional.

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Why does practising while distracted not seem to work?

Because attention has a chemical signature. Cholinergic input from the basal forebrain raises signal-to-noise in the cortex and gates whether synapses in the attended circuit are eligible for lasting change. Experimentally, pairing a stimulus with cholinergic activation is sufficient to reorganise sensory cortex around that stimulus. Repetitions performed with attention elsewhere are therefore less likely to consolidate, regardless of how many you do.

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Can I train my ability to stay patient in long sessions?

Patience appears to be substantially state-dependent rather than fixed, which cuts both ways. It is degraded by sleep loss, energy restriction and accumulated stress, so protecting those protects patience. Behaviourally, pre-committing to a written plan, segmenting long efforts into defined stages, and rehearsing the uncomfortable portion in training all reduce the number of decisions you have to make while your time horizon is shortened.

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Is nicotine useful for focus, given acetylcholine is involved?

Nicotine does act on nicotinic acetylcholine receptors and does have measurable acute effects on attention in some studies. It is also highly addictive, and there are cardiovascular and other health considerations, so it is not something this article recommends. Any decision involving nicotine, including pouches and gum, should be discussed with a doctor rather than reasoned from receptor pharmacology.

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How does caffeine fit into this?

Caffeine works mainly by blocking adenosine receptors rather than by acting directly on these three systems, but adenosine antagonism has downstream effects on catecholaminergic signalling, which is part of why it increases alertness. It shifts you rightwards along the arousal axis in Figure 2, which is helpful for a maximal attempt and potentially counterproductive before a complex decision task. Article 5.20 covers the evidence in detail.

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Recommended videos

Each video below was chosen because it covers a specific part of this article in more depth than text alone allows.

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Related reading on FitXplor

• 5.6 Neurotransmitters and Neuromodulators
• 5.7 The Dopamine System
• 5.3 Attention, Arousal, and Performing Under Pressure
• 5.5 The Athlete’s Brain
• 1.5 The Nervous System and Athletic Performance

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References

Aston-Jones, G., & Cohen, J. D. (2005). An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annual Review of Neuroscience, 28, 403–450.

Yerkes, R. M., & Dodson, J. D. (1908). The relation of strength of stimulus to rapidity of habit-formation. Journal of Comparative Neurology and Psychology, 18(5), 459–482.

Cools, R., Nakamura, K., & Daw, N. D. (2011). Serotonin and dopamine: unifying affective, activational, and decision functions. Neuropsychopharmacology, 36(1), 98–113.

Miyazaki, K. W., Miyazaki, K., & Doya, K. (2012). Activation of dorsal raphe serotonin neurons underlies waiting for delayed rewards. The Journal of Neuroscience, 32(31), 10451–10457.

Crockett, M. J., Clark, L., & Robbins, T. W. (2009). Reconciling the role of serotonin in behavioral inhibition and aversion. The Journal of Neuroscience, 29(38), 11993–11999.

Moncrieff, J., Cooper, R. E., Stockmann, T., Amendola, S., Hengartner, M. P., & Horowitz, M. A. (2023). The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry, 28(8), 3243–3256.

Sarter, M., Gehring, W. J., & Kozak, R. (2006). More attention must be paid: the neurobiology of attentional effort. Brain Research Reviews, 51(2), 145–160.

Kilgard, M. P., & Merzenich, M. M. (1998). Cortical map reorganization enabled by nucleus basalis activity. Science, 279(5357), 1714–1718.

Hasselmo, M. E., & Sarter, M. (2011). Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology, 36(1), 52–73.

Zhang, J., Zhu, Y., Zhan, G., et al. (2014). Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons. The Journal of Neuroscience, 34(12), 4418–4431.

Berridge, C. W., & Waterhouse, B. D. (2003). The locus coeruleus-noradrenergic system. Brain Research Reviews, 42(1), 33–84.

Meeusen, R., Watson, P., Hasegawa, H., Roelands, B., & Piacentini, M. F. (2006). Central fatigue: the serotonin hypothesis and beyond. Sports Medicine, 36(10), 881–909.