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VOL. 74 (3), 387-408, 2008 FINE TUNING NEUROMODULATION BY ADENOSINE...

substances, also abundant in the brain, as GABA, will have the ability
to inhibit glutamatergic transmission?

In the brain, besides the classical neurotransmitters, there are
substances that behave as neuromodulators of neurotransmitters and
even of neuromodulators themselves see e.g. (35). These substances,
in contrast with classical neurotransmitters, are not contained in
vesicles, are not released through exocytosis but through transporters,
and can be released post-synaptically to act both pre- and post-
synaptically on specific receptors. One of these substances intensively
studied in the last 25 years is adenosine.

Adenosine exists in all cells, and is released from apparently all
insulted cells, including neurons and glial cells. Once in the
extracellular space, adenosine modifies cell functioning by operating
G protein-coupled receptors.

Adenosine as a neuromodulator

Adenosine is indeed consensually recognised as a very important
substance in the homeostasis of the cells of the nervous system, being
in relation to cardio-protection once named «a signal of life» (11). It
modulates the activity of the nervous system by acting pre-synaptically
(by inhibiting or facilitating transmitter release), post-synaptically,
and/or non-synaptically. The way adenosine is doing this is through
activation of physiologically relevant high affinity adenosine receptors
(A1, A2A) as well as of a lower affinity receptors (A2B, A3), which might
be relevant in pathological conditions (see 31). Besides affecting
directly the neuronal cells, adenosine receptor activation also
influences the action of other neurotransmitters as well as of other
neuromediators. Because adenosine uses very subtle manners to
participate in these interactions, it acts as a fine tuner, considering
that in this way, adenosine is involved in a very sophisticated interplay
between its own receptors and the receptors for other synaptic
mediators. From these modulatory actions it is possible to anticipate
potential therapeutic applications, especially when these actions are
mediated by high-affinity adenosine A2A receptors in regions where
clear functions have been identified. The A2A receptor is highly
expressed in the striatopallidal GABAergic neurones and expressed in

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