Caffeine and the Brain: An Overview - Caffeine: Chemistry, Analysis, Function and Effects - page 255

crine function. Moreover, serotonin exerts its effects on functions such as pain,
feeding, memory and mood and for all these reasons it was considered of
interest to study whether caffeine affects serotonin neurotransmission in vivo.
Among the studies that addressed this issue, it was reported that caffeine,
administered locally, significantly increases hippocampal serotonin transmis-
sion (Okada et al 1997). However, in another study it was shown that caffeine
(1.7 mg kg 21 i.p.) could reduce the increases of serotonin in the hippocampus
after restraint stress (Yamato et al 2002), suggesting that caffeine may exert a
modulatory effect on this neurochemical response to stress.

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14.4 Effects of Caffeine on Mechanisms of Synaptic
Plasticity
Caffeine affects synaptic activities, either pre- and post-synaptically, by
regulating excitatory neurotransmitters release and by affecting NMDA and
non-NMDA receptors activities (He et al 2004). By acting onto adenosine A 1
receptors, via cAMP-dependent long-term potentiation (Lu et al 1999),
caffeine also affects repetitive synaptic activities at the basis of long-term
changes in synaptic efficiency in CA1 hippocampal neurons. Recently, and in
addition to these mechanisms that involve caffeine in synaptic plasticity,
caffeine has also been demonstrated to activate ERK in rodents' brain in vivo
(Valjent et al 2004; Acquas et al 2010). ERK kinases are enzymes that act by
sequential phosphorylation (MAPK-ERK-kinase-kinase activates MAPK-
ERK-kinase which, in turn, activates MAPK, a kinase family of which
phosphorylated ERK are the best known and characterized) (Sweatt 2004).
The interest on these kinases ubiquitously present in the mature brain
originated from the observation of their involvement in many central functions
such as memory formation and consolidation in associative learning-based
tasks, memory formation-related synaptic plasticity (Huang et al 2010), early-
and late-phase of long-term potentiation, as well as in synapse formation and
function and after physiological stimulation. Caffeine has been shown to
significantly increase pERK expression in the superficial and deep layers of the
PFCx and in the Cg 1 -Cg 2 cortices (Acquas et al 2010) while failing to elicit
pERK in M 2 cortex (Acquas et al 2010; Valjent et al 2004) and in other brain
regions such as piriform cortex, basolateral amygdala, hypothalamus, lateral
septum, ventral tegmental area, AcbSh and AcbC (Acquas et al 2010; Valjent
et al 2004). This differential activation of ERK by caffeine in distinct brain
regions suggests that there may be a differential impact of caffeine on these
structures in terms of ERK-mediated plasticity. In particular, failure of
caffeine to activate ERK in M 2 cortex indicates that the psychomotor
properties of caffeine do not require ERK activation in this cortical region. On
the other hand, the observation that caffeine activates ERK in the PFCx and
Cg 1 -Cg 2 cortex, in a DA D 1 receptor-dependent and -independent manner,
respectively, supports to the interpretation that D 1 receptor-dependent
phosphorylation of ERK in the PFCx by caffeine is specific for that cortical