1986b). Bailey et al.(1992, 1993a) further estab-
lished the relationship between fatigue and
increased concentrations of 5-HT and 5-HIAA
in various brain regions during treadmill
running. These data, however, cannot differenti-
ate between intra- and extracellular concentra-
tions of these substances and therefore are not
sufficient to conclude that fatigue is necessarily
associated with increased release of 5-HT from
serotonergic neurones. Techniques involving
microdialysis are necessary for this purpose
(Meeusen & De Meirleir 1995). Good evidence
using microdialysis is now available to show that
5-HT release from serotonergic nerve terminals
does increase during treadmill running and that
this is increased further by tryptophan adminis-
tration (Meussen et al. 1996, 1997). However, no
such studies have been done during exercise to
fatigue.
Other studies have addressed the potential
functional role of altered brain 5-HT activity on
exercise fatigue. Bailey et al.(1992, 1993a, 1993b)
did a series of experiments involving drug-
induced alterations in brain 5-HT activity during
exercise to fatigue in rats. It was hypothesized
that administration of drugs known to specifi-
cally increase brain 5-HT activity (5-HT agonists)
would result in early fatigue, whereas drugs that
decrease brain 5-HT activity (5-HT antagonists)
would delay it. The results show that run time to
fatigue was decreased following administration
of the 5-HT receptor agonists m-chlorophenyl
piperazine and quipazine dimaleate, whereas
run time was increased with a 5-HT receptor
antagonist (LY-53857). The supposition that these
drug-induced effects resulted from altered neu-
rotransmitter function in the brain is supported
by the observation that fatigue could not be
explained by alterations in body temperature,
blood glucose, muscle and liver glycogen, ornutrition, neurotransmitters and cns fatigue 173
TRPTRPTRPTRP TRP TRP5-HT5-HT5-HT5-HT5-HTTRP TRP
TRPAAAFFAFFA FFA
FFAFFA FFABCAAf-TRP
BCAAFFAB r a i n C a p i l l a r yTRPTRPTRP
TRP5-HT5-HT5-HTTRPAAAFFAFFABCAA
BCAABCAATRPf-TRP
BCAAFFAB r a i n C a p i l l a r y(a)(b)Fig. 12.1The primary components of the
central fatigue hypothesis. (a) At rest,
plasma concentration of BCAA, FFA and
TRP (bound and unbound to albumin (A))
and their proposed effects on transport of
TRP across the blood–brain barrier for the
synthesis of serotonin (5-HT) in
serotonergic neurones. (b) Reflects the
increases in FFA, f-TRP and f-TRP/BCAA
that occur during prolonged exercise. The
resulting increase in brain 5-HT synthesis
can cause central fatigue.