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

although indirectly, adenosine inhibitory (A1) receptors might control
GABAergic functioning. Direct excitation of GABAergic nerve

terminals by adenosine might occur through A2A receptors (31).

Adenosine as a modulator of other neuromediators

Besides its direct pre- and post-synaptic actions on neurons,
adenosine is rich in nuances of priming, triggering and braking the
action of several neurotransmitters and neuromodulators. Adenosine
is also able to «synchronize» or «desynchronise» receptor activation
for neuropeptides such as calcitonin gene-related peptide (CGRP)
and vasoactive intestinal peptide (VIP), nicotinic autofacilitatory
receptors, NMDA receptors, metabotropic glutamate receptors, as
well as adenosine own receptors (37). Also the inhibitory action of
adenosine A2A and A2B receptors on nitric oxide (NO) production and
iNOS expression in glial cells (6) can constitute a partnership aiming
neuronal protection after insults. Of particular importance is the
recent finding by Chao (6) that TrkB neurotrophin receptors can be
activated in the absence of neurotrophins, providing that A2A
receptors are activated. The authors emphasize that although there
are suggestions proposing the use of neurotrophins in Alzheimer’s
dementia, amyotrophic lateral sclerosis and peripheral sensory
neuropathy, it has been difficult to deal with delivery and
pharmacokinetics of these molecules. Thus, the possibility of
promoting trophic effects by manipulating the degree of activation
of A2A receptors, may prove highly relevant in neurodegenerative
disorders where sustained actions on survival signalling pathways
are needed.

Selective activation of adenosine A2A instead of A1 receptors

Adenosine A1 and A2A receptors can co-exist in the same nerve
terminal (35). Evidence for this arrived from the observation that an
A1 receptor agonist acting pre-synaptically inhibits and an A2A
receptor agonist acting also presynaptically enhances the amplitude
of endplate potentials recorded intracellularly from a single endplate,
which in the case of the striated muscle receives input from only one

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