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

ability of A1 receptors to inhibit NMDA currents is the basis of the
A1 receptor mediated inhibition of synaptic plasticity (LTP and LTD)
as well as contributes to A1 receptor mediated neuroprotective
actions (31).

To summarize this point I would like to stress that adenosine
exerts pre-, post- and non-synaptic effects by acting on high affinity
receptors: A1 and A2A. There are also low affinity receptors: A2B
and A3, but so far their activation is not apparently related with
neuromodulation with potential implications for neuroprotection.

Adenosine-Receptor interactions with Adenosine transporter

NECA activates adenosine tranport in cultured chromaffin cells
(8). This was the first work to making connection between adenosine
receptors and adenosine transport. Recently (24), using hippocampal
synaptosomes described the nature of this receptor, an A2A receptor,
which when activated enhances adenosine uptake, and that A2A
receptor activation enhances adenosine release. So, it appears that
A2A receptors regulate adenosine transporters influencing the
extracellular availability of this nucleoside.

HYPOXIA RELEASES ADENOSINE

It is well established and consistent that after hypoxia/ischemia
insults there is release of adenosine into the synaptic cleft. This
adenosine is responsible for the inhibition of synaptic transmission
during hypoxia, since the A1-receptor antagonist, a xanthine
derivative, DPCPX, attenuates this inhibitory effect of hypoxia by
at least 50%. Therefore, the inhibitory effect of hypoxia is a
consequence of A1-receptor activation by huge amounts of adenosine
being released (34). One interesting aspect in the adenosine effect
is that if one tries to recover from hypoxia in the presence of the A1
antagonist, DPCPX, the recovery is never complete as it happens
during recovery without A1 blockade. This suggests that adenosine is
absolutely needed for complete recovery from hypoxia. This effect of
adenosine is a consequence of pre-synaptic inhibition of glutamate

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