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J. A. RIBEIRO AN. R. ACAD. NAC. FARM.

nerve ending. The coexistence of both subtypes of high affinity

adenosine receptors prompted the question on how adenosine

chooses to activate A1 or A2A receptors, and under which conditions
does it discriminate between these receptors. It appears that instead

of the classical view that endogenous adenosine activates A1 receptors
regardless of whether it is released as such or formed from adenine

nucleotides, adenosine formed from adenine nucleotides acts

preferentially on A2A receptors, and adenosine released as such acts
preferentially on A1 receptors (9). This may result from different
localization of A1 and A2A receptors in relation to adenosine release
sites and ecto-5’-nucleotidase localization. An indication that burst-

like adenosine formation from released adenine nucleotides might

be, at least in part, responsible for its preferential action on A2A
receptors, is the finding that when motor nerve endings are

stimulated at low frequency, i.e., under conditions where smaller

amounts of adenine nucleotides are released, the ecto-5’-nucleotidase

inhibitor, a,b-methylene ADP (AOPCP), enhances (31) rather than

inhibits acetylcholine release. Indeed, the pattern of neuronal firing

influences the pattern of purine release and extracellular formation,

and in consequence, influences the way purines modulate synaptic

transmission. High frequency stimulation favours ATP release, and

adenosine formation, which preferentially activates adenosine A2A
receptors activation, whereas low frequency stimulation favours

adenosine release, and preferential adenosine A1 receptor activation
(see 31).

Modulation of NMDA receptors

In the isolated rat hippocampal neurons, A1 receptor activation
inhibits NMDA receptor-mediated currents (34). In the hippocampus
A1 receptors are also inhibitory of glutamate release and A2A-receptors
facilitate glutamatergic synaptic transmission (31). Interestingly, the
inhibitory action of A1 receptor agonists on NMDA receptor mediated
currents in hippocampal neurons is observed in a concentration
range compatible with a tonic inhibitory action of adenosine. Due to
the important role played by NMDA receptors in synaptic plasticity
phenomena, as well as in neuronal injury after prolonged
stimulation/depolarisation conditions, it is conceivable that the

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