While A Rs communicate mainly with the D R subtype

While A1Rs communicate mainly with the D1R subtype [36], A2AR and D2R interaction occurs mainly in basal ganglia. D2Rs colocalizes with A2ARs in this Fmoc-Leu-OH area where they are preferentially localized postsynaptically in the soma and dendrites of GABAergic striatopallidal neurons [69]. This interaction plays a very important role in striatal function. A2AR–D2R interaction provides an example of the capabilities of information processing by just two different G protein-coupled receptors. Interestingly, here is evidence for the coexistence of two reciprocal antagonistic interactions between A2ARs and D2Rs in the same neurons. In one type of interaction, A2ARs and D2R are forming heteromers and, by means of an allosteric interaction, A2ARs counteracts D2Rs-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striatopallidal neuron. This antagonistic interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2ARs and D2Rs that do not form heteromers and takes place at the level of adenylyl cyclase [26] indicating two different populations of postsynaptic striatal A2ARs. In summary, signaling through A2ARs and D2Rs is distinctive and synergistic, supporting their unique and yet integrative roles in regulating neuronal functions when both receptors are present. The results of the above mentioned studies support the notion that receptor heteromers may be used as selective targets for drug development. Their opposing roles in regulating neuronal activities, such as locomotion and alcohol consumption, are mediated by their opposite actions on adenylate cyclase, which often serves as “co-incidence detector” of various activators [79]. On the other hand, the neural actions of A2ARs and D2Rs are also, at least partially, independent of each other, as indicated by studies using D2Rs and A2ARs knock out mice. Studies on mice and monkeys suggest that some degree of dopaminergic activity is needed to obtain adenosine induced antagonistic effects on motor activity. The blockade of dopaminergic neurotransmission counteracts the antagonistic effect induced by adenosine [24,26].
Interaction between adenosine receptors and NMDA receptors Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. In most brain areas, glutamate mediates fast synaptic transmission by activating ionotropic receptors of the AMPA, kainate and NMDA subtype. Additionally, NMDA receptors play a critical role in synaptic plasticity, synaptic development and neurotoxicity. In a recent study, Arrigoni et al. [6] have investigated the role of exogenous and endogenous adenosine in regulating synaptic glutamatergic transmission. From their electrophysiological results a presynaptic site of action for A1R receptors on glutamatergic afferents was suggested by the following: (1) adenosine did not affect exogenous glutamate-mediated current, (2) adenosine reduced glutamatergic miniature EPSC frequency, without affecting the amplitude, and (3) inhibition of the evoked EPSC was mimicked by an A1R agonist but not by an A2R agonist. Applicable with these findings is the study of [46,46] indicated that endogenous adenosine present in the extracellular fluid of hippocampal slices inhibits NMDA receptor-mediated dendritic spikes as well as AMPA/kainate receptor-mediated excitatory synaptic potentials by activation of A1Rs in CA1 pyramidal cells and with results of [75] showing that the activation of A1Rs by ambient adenosine depressed field potentials in the striatum. The effect of adenosine in the striatum [75] or hippocampus [56] has not been found in A1R knockout mice, and clearly demonstrates the involvement of A1Rs. The involvement of A1Rs was also supported by experiments using a selective receptor ligand. On the other hand, NMDA is known to increase the extracellular level of adenosine via bi-directional adenosine transporters or from released adenine nucleotides degraded by a chain of ectonucleotidases [15,37].