Caffeine and the Brain: An Overview - Caffeine: Chemistry, Analysis, Function and Effects - page 253

D 2 receptors. This action is mediated also by caffeine while blocking the
stimulatory action exerted by adenosine via A 2A receptors (Fredholm et al
1999).
Adenosine is an endogenous sleep factor and it may affect sleep and EEG
arousal through modulation of basal forebrain cholinergic projections to the
cortex. However, an alternative hypothesis has recently suggested the
involvement in these effects of an A 1 and A 2A receptors-mediated mechanism
of modulation of ACh transmission in the PFCx as responsible of the
activation of a descending pathway to the pontine reticular formation (Van
Dort et al 2009). The effects of systemic administration of caffeine on ACh
transmission have been studied in freely moving rats implanted with concentric
microdialysis probes in the PFCx (Acquas et al 2002). Administration of
caffeine at doses that elicit behavioral stimulation (0.25-5.0 mg kg 21 i.v.) dose-
dependently increases ACh dialysate concentrations (Figure 14.3), an effect
also reproduced by the selective A 1 and A 2A receptor antagonists, DPCPX and
SCH 58261 respectively (Acquas et al 2002). Interestingly, the ability of the
acute administration of caffeine to stimulate ACh transmission in the PFCx is
also present after a regimen of chronic (25 mg kg 21 twice a day for 7 days)
caffeine administration whereas the stimulation of DA transmission and of
motor activity by caffeine is prevented by such chronic treatment.
These findings suggest that caffeine-induced stimulation of DA transmission
in the PFCx might be related with a role of motor activation in the effects of
caffeine on PFCx DA (Acquas et al 2002). In animals tolerant to the
locomotor stimulant effects of caffeine, on the other hand, the unmodified
ability of caffeine to stimulate PFCx ACh transmission might be related to the
EEG desynchronizing effects of caffeine (Acquas et al 2002). In vivo brain
microdialysis studies have also shown that caffeine (3-30 mg kg 21 p.o.) dose-
dependently increases ACh transmission from rats' hippocampus suggesting
that also hippocampal ACh transmission is under tonic inhibitory control of
endogenous adenosine.
The effects of caffeine on in vivo neurotransmission of noradrenaline have
been studied as well. Thus, in a microdialysis study in the hippocampus it was
shown that neither systemic administration of caffeine (30 mg kg 21 p.o.) nor
its local perfusion (1 mmol L 21 ) could alter the extracellular concentrations of
noradrenaline of awake, freely moving rats (Carter 1997). In this study, it was
also shown that baseline and K + -stimulated extracellular concentrations of
noradrenaline

d n 0 t 2 n g | 7

are regulated by a 2 adrenoceptors and not by adenosine

receptors (Carter 1997).
The ascending serotoninergic system, which originates in the brainstem, is
considered a portion of the ascending reticular activating system and
contributes to behavioral inhibition. Interestingly, although the serotoninergic
system is not directly involved in arousal, its activity is maximal during the
waking state, decreases during slow-wave sleep and stops during fast-wave
sleep. In particular, the activity of pontine and medullary serotoninergic
neurons facilitates motor output and coordinates autonomic and neuroendo-