Purinergic Signalling (2007) 3:299–310 cell trophism according to its extracellular concentrations, distinct cell populations involved, differential expression and recruitment of P2 receptors and of more or less sus- tained stimulation of the same receptor. Balancing these effects may be relevant in the post-ischemic brain, when a neuroregenerative process could promote tissue repair [47]. On this basis, determination of ATP extracellular concen- trations at various times after ischemia induction may help to identify which types of receptors may be stimulated under ischemia and explain the role of detrimental versus trophic ATP during ischemia. ATP present in the extracellular space is rapidly metabolised by membrane-bound NTPDase. Extracellular ATP concentrations, evaluated in the brain to date, have been underestimated, since it has not been possible to selectively inhibit ecto-NTPDase. In fact, the selective inhibitor ARL 67156, tentatively used thus far to inhibit ecto- NTPDase, interferes with the ATP assay method [29]. Role of adenosine in cerebral transmission under normoxic conditions Adenosine exerts an important tonic modulation of synaptic transmission in the brain. This tonic inhibition of synaptic transmission is evoked by stimulation of A1 receptors, as demonstrated in several brain regions, such as the hippo- campus, striatum and olfactory cortex [48, 49]. The inhibitory effect of adenosine A1 receptor stimulation has a pre- and postsynaptic component. Activation of the presyn- aptic A1 receptors reduces Ca2+ influx through the preferen- tial inhibition of N-type and, probably, Q-type channels [50, 51]. Inhibition of presynaptic calcium currents decreases transmitter release [52], and adenosine, by stimulation of A1 receptors, has been found to inhibit the release of virtually all classical neurotransmitters: glutamate, acetylcholine, dopa- mine, noradrenaline and serotonin (see in [53]). In particular, powerful suppression of glutamate release from presynaptic terminals has been described in the hippocampus [54, 55], where adenosine A1 receptor activation reduces the number of quanta released (but not the size of individual quanta nor postsynaptic glutamate receptor sensitivity) in the Schaffer collateral-commissural pathway [56]. The postsynaptic effect of A1 receptors consists of direct hyperpolarisation of neurones via activation of GIRK channels (Kir 3.2 and 3.4 channels: potassium inward rectifiers) [57, 58]. Endogenous adenosine exerts tonic inhibition of excitatory neurotrans- mission. The selective A1 antagonist, DPCPX, causes a 15% increase in synaptic potential amplitude in in vitro brain slices [59]. This is an expected result in a brain region where the adenosine concentration at a receptor level was calculated around 200 nM [59, 60] and A1 receptors, whose affinity for adenosine is in the low nanomolar range, are highly ex- pressed. These data are confirmed by the fact that, in slices 303 taken from homozygous A1 receptor knockout mice, no evidence was found for an endogenous inhibitory action by adenosine in the Schaffer collateral pathway in the CA1 region of the hippocampus or at the mossy fibre synapses in the CA3 region [61]. Opposite effects from A1-mediated synaptic inhibition are elicited by A2A receptor activation, which has been shown to mediate excitatory actions in synaptic function [62–64]. In the hippocampus in vitro, A2A receptor stimulation results in a Ca2+-dependent release of acetylcholine [65, 66]. Further- more, the application of CGS 21680, a selective A2A receptor agonist, decreases the ability of A1 receptor agonists to inhibit excitatory neurotransmission [9, 67]. This effect suggests that A2A receptor stimulation increases synaptic transmission through A1 receptor desensitisation [68, 69]. However, there is also evidence that A2A receptors increase excitatory amino acid release. In fact, the selective stimulation of adenosine A2A receptors augments the amount of glutamate released in the hippocampus and striatum of young rats [70–72]. In spite of the excitatory role in neurotransmission brought about by A2A receptors, the net effect of adenosine is an inhibitory tonus on neurotransmission, in accordance with observations suggesting that activation of A2A receptors requires protracted stimulation to induce evident effects on synaptic transmission [59]. It is worth noticing that the role of A2A receptors in the striatum is recently gaining interest in light of their heterodimerisation with D2 dopamine receptors. The association between A2A and D2 receptors results in an antagonistic interaction that provides a rationale for evaluat- ing A2A-selective antagonists in Parkinson’s disease, sup- ported by epidemiological evidence indicating an inverse relationship between caffeine consumption and the risk of developing this pathology [73, 74]. It was suggested that A2A antagonists not only provide symptomatic relief but also decelerate dopaminergic neurone degeneration in patients. Discrepancies about the role of adenosine A3 receptors in the brain are present in the literature. Activation of this receptor subtype has been associated with both excitatory and inhibitory effects, even in the same brain region. An excitatory role of A3 receptors has been supported by evidence indicating that, in the rat hippocampus, their activ- ation attenuates LTD and allows induction of LTP elicited by a subliminal weak-burst protocol [75]. In addition, in the same brain area, A3 receptor activation through a selective adenosine A3 agonist has been shown to antagonize the adenosine A1 receptor-mediated inhibition of excitatory neurotransmission [8]. Moreover, A3 receptor stimulation always attenuates the inhibition of hippocampal slice neuro- transmission, in a PKC-dependent manner, caused by pre- synaptic metabotropic glutamate receptors [76]. Whole-cell patch clamp recordings in CA3 hippocampal pyramidal neurones demonstrate that A3 receptor activation results in a significant potentiation of high threshold hippocampal Ca2+