Caffeine and the Brain: An Overview - Caffeine: Chemistry, Analysis, Function and Effects - page 256

region. Interestingly, despite the fact that D 1 receptors are mostly present in
the PFCx and Cg 1 -Cg 2 cortices, whereas D 4 receptor subtypes are mostly
present in the M 2 cortex, these observations are in agreement with the finding
that blockade of D 1 receptors prevents caffeine-elicited ERK activation in the
PFCx on one hand, whereas, on the other, the lack of D 1 receptors-mediated
control of caffeine-elicited pERK in the Cg 1 -Cg 2 cortices indicates that ERK
activation might be the result of multisynaptic mechanisms (Acquas et al
2010). Thus, although the Cg 1 -Cg 2 cortex is a D 1 receptor-rich cortical region,
blockade of D 1 receptors fails to critically regulate caffeine-mediated ERK
phosphorylation (Acquas et al 2010). These observations indicate that
multisynaptic mechanisms must be taken into account in order to interpret
the mechanism(s) of caffeine activated ERK phosphorylation in different
cortical regions and overall suggest to investigate further the molecular
mechanism(s) by which caffeine-mediated synaptic plasticity may take place in
distinct cortical regions.
Recent theories on the neurobiological basis of addiction indicate that this
behavioral disturbance may have at his basis a failure of the molecular
mechanisms responsible of impulse control and associative learning and,
interestingly, pERK, has been attributed a critical role in these mechanisms
(Lu et al 2006). Thus, as a further example of the functional significance that
can be highlighted by detection of activated ERK in different brain regions, it
is worth mentioning, in this regard, the lack of ERK activation in the AcbSh
and AcbC following the administration of caffeine, at doses that significantly
enhance pERK expression in the PFCx and Cg 1 -Cg 2 cortices (Acquas et al
2010). The Acb and the extended amygdala have been indicated as anatomical
transition structures between motor and motivational responses and DA
transmission in these regions has been pointed out as the main neurochemical
mechanism that mediates both motor and motivational properties of addictive
drugs (Di Chiara 2002). Thus, based on the evidence that DA transmission in
the Acb and extended amygdala is increased by drugs with addictive potential,
it was postulated that the preferential increases of DA transmission in the
AcbSh compared to the AcbC represent the common neurochemical trait of
addictive drugs belonging to different pharmacological classes (Di Chiara
2002). Interestingly, on the post-synaptic side, the activation of ERK was
suggested to be differentially activated by addictive and non-addictive drugs, in
distinct regions of the mouse brain (Valjent et al 2004). Thus, based on these
premises, and in order to contribute to the ongoing debate on the possibility to
exclude (or include) caffeine in the list of the addictive substances, we found
that while failing to stimulate DA transmission in the AcbSh and AcbC, at
doses able to stimulate DA and ACh transmissions in the PFCx (Acquas et al
2002), caffeine also fails to elicit pERK in the AcbSh and AcbC (Acquas et al
2010). These results brought us to conclude that failure to stimulate DA
transmission and elicit pERK in the Acb justifies, from the preclinical point of
view, the exclusion of caffeine from the list of the restricted substances (APA

d n 0 t 2 n g | 7