simply heightened arousal. Because they are also
related to peripheral metabolic effects, the fol-
lowing topics are of special interest in a discus-
sion of caffeine’s central effects: adenosine
receptor antagonism, lowered perceived exer-
tion and the central fatigue hypothesis.
Adenosine receptor antagonism
Since caffeine can freely pass through the
blood–brain barrier (Nehlig et al. 1992), its con-
centration in the brain and CNS increases rapidly
following ingestion, in concert with changes
in other body tissues (Daly 1993). Caffeine
increases brain neurotransmitter concentration,
causing increases in spontaneous locomotor
activity and neuronal firing in animals (Nehlig et
al.1992). It is generally accepted that the mecha-
nism for neurotransmitter increases is adenosine
receptor antagonism and high adenosine recep-
tor levels in the brain support this hypothesis
(Fernstrom & Fernstrom 1984; Snyder 1984; Daly
1993; Fredholm 1995).
Adenosine is both a neurotransmitter and neu-
romodulator, capable of affecting the release of
other neurotransmitters (Fernstrom & Fernstrom
1984). Adenosine and adenosine analogues gen-
erally cause lowered motor activity, decreased
wakefulness and vigilance, and decreases in
other neurotransmitter concentrations. Caffeine
and adenosine receptor antagonists have the
opposite effect by blocking the adenosine recep-
tors. It is generally believed that the inhibition
(adenosine) or stimulation (caffeine) of neuro-
transmitter release is presynaptic (Snyder 1984;
Fredholm 1995). It has been demonstrated that
caffeine increases the concentration, synthesis
and/or turnover of all major neurotransmitters,
including serotonin, dopamine, acetylcholine,
noradrenaline and glutamate. These neurotrans-
mitters are all inhibited by adenosine. The exact
consequences of these changes in neurotransmit-
ters with regards to performance is currently
not known. Both dopamine and serotonin levels
have been implicated in the central effects of caf-
feine on fatigue and behaviour (Fernstrom &
Fernstrom 1984; Daly 1993), and in the develop-
386 nutrition and exercise
ment of central fatigue exclusive of caffeine
ingestion (Davis & Bailey 1997). It has been sug-
gested that an increase in excitatory neurotrans-
mitters could lead to decreases in motorneurone
threshold, resulting in greater motor unit recruit-
ment (Waldeck 1973) and subsequently lower
perceived exertion for a given power output
(Nehlig & Debry 1994; Cole et al. 1996). However,
this theory has not been demonstrated during
exercise, although it continues to be cited as a
potential mechanism (Nehlig & Debry 1994; Cole
et al. 1996).
Complicating the effects of caffeine on adeno-
sine antagonism is the existence of two main
classes of adenosine receptors, A 1 and A 2 (Snyder
1984; Graham et al. 1994), each having differing
affinities for endogenous adenosine and xan-
thines, and affecting the release of different neu-
rotransmitters (Daly 1993) Likewise, antagonism
of these receptors is dependent on the caffeine
concentration, which will either inhibit (A 1 ) or
stimulate (A 2 ) adenylate cyclase, leading to
differential effects and possibly explaining the
biphasic response to caffeine. Increasing caffeine
doses are stimulatory, but very high physiologi-
cal doses are depressant (Snyder 1984). As well,
some adenosine antagonists display the same
affinity as xanthines for adenosine receptors, but
do not cause the same effects (Snyder 1984; Daly
1993). Finally, the binding of caffeine to benzo-
diazepine receptors and the relationship to
gamma-aminobutyric acid (GABA) and excita-
tory amino acids is currently being explored
(Nehliget al. 1992; Daly 1993). Some authors
assert that adenosine receptor antagonism, while
likely the primary mechanism, cannot account
for all of caffeine’s actions on the CNS (Graham
et al. 1994).Ratings of perceived exertion
One quantifiable aspect of caffeine’s central
effects is a lower rating of perceived exertion
(RPE) during exercise. Several studies have
demonstrated that (i) RPE at a standard power
output was lower in subjects following caffeine
ingestion than in controls (Costill et al. 1978), and