CNS fatigue is also thought to be the most
likely explanation of fatigue that accompanies
viral or bacterial infections, recovery from injury
or surgery, chronic fatigue syndrome, depres-
sion, ‘jet lag’ and meal-induced sleepiness and
fatigue (Davis & Bailey 1997). However, a full
understanding of the causes of fatigue in these
situations will await future studies designed to
provide plausible neurobiological mechanisms
to explain the fatigue.
Progress in this area is minimal, but much
recent interest has focused on hypotheses involv-
ing exercise-induced alterations in neurotrans-
mitter function as possible explanations for
central fatigue. Alterations in serotonin (5-
hydroxytryptamine, 5-HT), noradrenaline,
dopamine and acetylcholine (ACh) have all
been implicated as possible mediators of cen-
tral fatigue during stressful situations, including
strenuous physical exercise. These neurotrans-
mitters are known to play a role in arousal,
motivation, mood, sleepiness and other
behaviours/perceptions that, if adversely af-
fected, could impair physical and mental perfor-
mance. These neurotransmitter hypotheses also
provide the basis of new intriguing nutritional
strategies designed to improve performance by
offsetting exercise-induced alterations in these
neurotransmitters. This chapter will briefly
review the evidence for a possible role of 5-HT,
noradrenaline, dopamine and ACh in central
fatigue and then provide a more detailed discus-
sion of possible nutritional strategies that may
limit CNS fatigue.
Brain 5-HT and CNS fatigue
The neurotransmitter serotonin (5-HT) has
received the most attention with respect to CNS
fatigue during prolonged exercise. Eric
Newsholmeet al.(1987) were the first to hypothe-
size such a role for brain 5-HT, and present some
of their findings in Chapter 11. It was argued that
regional increases in brain 5-HT activity could
cause central fatigue because of its well-known
role in sensory perception, arousal, lethargy,
sleepiness and mood. This hypothesis was of
172 nutrition and exercise
particular interest because both exercise and
nutrition could influence brain 5-HT metabolism
by affecting the uptake of tryptophan from the
blood into the brain. Subsequent studies have
confirmed certain aspects of this hypothesis, as
well as to test the potential role of carbohydrate
(CHO) and/or branched-chain amino acid
(BCAA) feedings as a way to limit CNS fatigue
involving 5-HT.
Increased brain 5-HT synthesis and metabo-
lism typically occurs in response to an increase in
the delivery of blood-borne tryptophan (TRP)
to the brain because the enzyme tryptophan
hydroxylase (rate limiting enzyme in 5-HT syn-
thesis) is largely unsaturated under physiologi-
cal conditions. Most of the TRP in blood plasma
circulates loosely bound to albumin, but it is the
unbound or free tryptophan (f-TRP) that is trans-
ported across the blood–brain barrier. This trans-
port occurs via a specific mechanism that TRP
shares with other large neutral amino acids,
most notably the BCAAs leucine, isoleucine and
valine. Thus, brain 5-HT synthesis will increase
when there is an increase in the ratio of f-TRP to
BCAAs in blood plasma (i.e. when f-TRP/BCAA
rises; Chaouloff et al.1986a). There are two pri-
mary reasons for this increase during exercise.
Note that clear differences in this mechanism
may exist at rest, during periods of stress and
in various clinical conditions (Curzon 1996).
During exercise, large increases in plasma free
fatty acids (FFAs) cause a parallel increase in
plasma f-TRP because FFAs displace TRP from
its usual binding sites on albumin. Small
decreases in plasma BCAAs also occur as they
are taken up into working muscle and oxidized
for energy (Fig. 12.1).
Studies in both rats and humans provide good
evidence that brain 5-HT metabolism increases
during prolonged exercise and that this is as-
sociated with fatigue (Davis & Bailey 1996).
Chaouloff’s initial work in rats demonstrated
that prolonged treadmill running increases the
plasma f-TRP/BCAA ratio, and brain and cere-
brospinal fluid levels of tryptophan, 5-HT and 5-
hydroxyindole acetic acid (primary metabolite
of 5-HT, 5-HIAA) (Chaouloff et al.1985, 1986a,