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It’s What’s Inside that Counts.  But What’s Inside?  The Role of Serotonin in Central Fatigue.

It’s What’s Inside that Counts. But What’s Inside? The Role of Serotonin in Central Fatigue.

A 20th century philosopher, by the name of Vince Lombardi, once observed that “Fatigue makes cowards of us all”, and never were wiser words spoken. Fatigue is truly your greatest enemy in endurance competition. But what is fatigue? And how can we combat it?

To begin with, let’s make the distinction between peripheral and central fatigue.

Peripheral fatigue basically refers to the tiredness in your muscles as competition wears on, where, deep down inside, your brain is saying it still wants to give more, but your body just won’t deliver. Central fatigue, on the other hand, refers to fatigue of the brain. In other words, “peripheral” is your body quitting, “central” is your brain quitting.

Central fatigue seems to, in general, receive much less attention from a scientific standpoint. Probably because there is a long standing dogma in sports that, with regards to competitive drive or inner fire, you either have it or you don’t.

However, the science says differently. The reality is that central fatigue has as much of a physiological basis as peripheral fatigue. But, as with anything related to the physiology of the brain, the mechanisms of central fatigue are incredibly complex and very poorly understood. One thing that is known, though, is that the levels and interactions of the neurotransmitters serotonin, dopamine and norepinephrine play a significant role (2, 3).

Today’s article that I will be reviewing, by Claghorn et al., in the upcoming July edition of Physiology & Behavior (1), delves specifically more into the role of serotonin in central fatigue.

It is a very interesting article which examined the effects of manipulating the serotonergic pathways in rats bred for high levels of running (HR), looking at both voluntary and forced endurance exercise, and compared these effects to control rats (C) who had not been so selectively bred.

The HR rats had been selectively bred for high voluntary wheel running. The idea being that these were rats that had a mitigated central fatigue response as compared to the C group rats. By testing the responses of serotonin antagonism and agonism in these rats, they sought to further examine the role of serotonin in central fatigue.

What they found was that administration of an antagonist to the 5-HT1A receptor (which itself normally inhibits serotonin release) led to decreased endurance on forced running in the HR group, down to the level of the C group rats. The intervention, however, had no effect on endurance in the C group. This would appear to support the theory that the HR group’s higher baseline endurance was mediated through lower serotonin output, since abolishing this response brought their endurance down to that of the C group.

They also found, though, that the response to a 5-HT1A agonist, on the other hand, had a dose-dependent effect on forced endurance, with low doses leading to a mildly improved performance, but higher doses actually having a negative effect on performance. And these effects were similar in both the HR and C groups. They speculate that this biphasic effect occurs because at low doses the agonist acts pre-synaptically, inhibiting serotonin release, and at high doses it acts post-synaptically, mimicking serotonin at the effector regions in the brain and spinal cord.

Finally, they found no difference between groups using either of these manipulations during the voluntary wheel running portion of the testing. This difference in results between the forced running and voluntary running lends support to the notion that voluntary running and forced running are governed by different neurobiological processes.

Their conclusion was that these results showed the importance of serotonin signaling in performance during both forced and voluntary exercise. And, more generally, that both forced and voluntary exercise can be affected by an intervention that acts primarily centrally.

Serotonin has received a good deal of attention in recent years with regards to its effects on central fatigue (2, 3). The evidence appears to show a consistent relationship between higher levels of serotonin in the brain and increased central fatigue (3). Of course, as with anything related to neurophysiology, the answer is obviously much more complex than just “more” or “less”. For example, much speculation has also been given to the concept that what is more important is the ratio of serotonin to dopamine rather than simply the levels of serotonin (2). But clearly serotonin is a big player in this process.

But how does that translate into helping our training?

Much of the focus has been given to the role of tryptophan (2, 3, 12). Tryptophan is a rate-limiting precursor in the synthesis of serotonin. Tryptophan is heavily protein bound in the bloodstream, with only the “free” (unbound) portion able to cross into the brain. By decreasing the amount of free tryptophan entering the brain, the theory goes, less serotonin should be produced and central fatigue should be mitigated.

To accomplish this, one approach is to increase the amount of branched chain amino acids, or BCAAs, in the bloodstream during endurance exercise. BCAAs (leucine, valine, and isoleucine) compete with free tryptophan for entry into the brain. A lower ratio of free tryptophan to BCAAs should lead to less tryptophan in the brain and, consequently, less serotonin being produced.

The evidence in human studies for BCAA administration and endurance performance, though has been equivocal, with some studies showing a benefit (5, 7) and others not (8, 9, 10, 11).

Various potential explanations have been given for the disparate results. There may not be a true benefit, or maybe the benefit is too small to be consistently seen. Often, small scale studies fail to show a benefit as the numbers of participants do not provide enough statistical power to detect a difference. Absence of evidence, as the old saying goes, isn’t evidence of absence.

Personally, though, I feel that differences in ammonia production may be a significant part of the explanation.

Ammonia, like serotonin, also is a contributor to central fatigue (6) and is a byproduct of the metabolism of BCAAs. Research protocols using higher doses of BCAAs will also lead to higher ammonia production. Many of the negative studies had a relatively broad spectrum of BCAA dosing and they did not make it clear which study participants benefited and which didn’t, only that, overall, no benefit was found. There appears to be a relationship between the BCAA dosing and the likelihood of a performance benefit (3). It could very well be that a sweet spot needs to be found, with enough BCAAs to give the benefit of less serotonin production, but not too much to lead to excessive ammonia production.

Another approach to decrease the amount of tryptophan entering the brain is to decrease the proportion of free tryptophan in relation to that which is protein bound. Fatty acids compete with tryptophan for protein binding (4). As exercise wears on and your body runs out of carbohydrate sources for oxidation, you begin to tap more into your fat stores, leading to more fatty acids in the blood stream. This, as the theory goes, leads to displacement of bound tryptophan from protein, and thus higher proportions of free tryptophan, which subsequently enter the brain leading to increased serotonin synthesis. By delaying this process of fat mobilization as much as possible through the administration of carbohydrates, central fatigue can theoretically be attenuated. This is why strategies aimed at increasing earlier fatty acid mobilization through low-glycemic index carbs may be ill-advised.

Regardless of the various controversies, central fatigue is undeniably a very complex physiological process. But the research continues to teach us more every day. And with every bit of new knowledge learned comes new questions. When it comes to competitive drive, “what’s inside” may count, but what actually IS inside is really the much bigger question.

1. Claghorn GC, Fonseca IA, Thompson Z, Barber C, Garland T Jr. Serotonin-mediated central fatigue underlies increased endurance capacity in mice from lines selectively bred for high voluntary wheel running. Physiol Behav. 2016 Jul 1;161:145-54.
2. Meeusen R, Watson P, Hasegawa H, Roelands B, Piacentini MF. Central fatigue: the serotonin hypothesis and beyond. Sports Med. 2006;36(10):881-909.
3. Blomstrand E: A role for branched-chain amino acids in reducing central fatigue. J Nutr 2006, 136(2):544S-547S.
4. Curzon G, Friedel J, Knott PJ. The effect of fatty acids on the binding of tryptophan to plasma protein. Nature. 1973;242:198–200.
5. Blomstrand E, Hassmen P., Ekblom B., and Newsholme E. A. Administration of branched-chain amino acids during sustained exercise – effects on performance and on plasma concentration of some amino acids. Eur J Appl Physiol Occup Physiol. 1991;63(2):83-88
6. Mutch BJ, Banister EW. Ammonia metabolism in exercise and fatigue: a review. Med Sci Sports Exerc. 1983;15(1):41-50.
7. Mittleman KD, Ricci MR, Bailey SP Branched-chain amino acids prolong exercise during heat stress in men and women. Med Sci Sports Exerc 1998 30:83–91
8. van Hall G, Raaymakers J S, Saris W H, and Wagenmakers A J. Ingestion of branched-chain amino acids and tryptophan during sustained exercise in man: failure to affect performance. J Physiol. 1995 Aug 1; 486(Pt 3): 789–794.
9. Madsen K, MacLean DA, Kiens B, Christensen D. Effects of glucose, glucose plus branched-chain amino acids, or placebo on bike performance over 100 km. J Appl Physiol (1985). 1996 Dec;81(6):2644-50.
10. Watson P, Shirreffs SM, Maughan RJ. The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment. Eur J Appl Physiol. 2004 Dec;93(3):306-14.
11. Cheuvront SN, Carter R 3rd, Kolka MA, Lieberman HR, Kellogg MD, Sawka MN. Branched-chain amino acid supplementation and human performance when hypohydrated in the heat. J Appl Physiol (1985). 2004 Oct;97(4):1275-82.
12. Newsholme EA, Blomstrand E. Branched-chain amino acids and central fatigue. J Nutr. 2006 Jan;136(1 Suppl):274S-6S.