In the brain, A1 and A2A are the major ARs.58 A1 receptor, the most abundant subtype, is widely distributed in the cortex, hippocampus, and cerebellum, while A2A receptor is mainly localized in the striatum and olfactory bulb.30 Presynaptically, A1 and A2A interact with adenosine to modulate the release of neurotransmitters.62 Postsynaptically, adenosine decreases cellular excitability through activation of A1Rs or inhibition of A2ARs.63 Thus, A1Rs impose an inhibitory brake on excitatory transmission, while A2A receptors engage in promoting excitatory effect.64 In general, A1R is considered a neuroprotective and A2A receptor is designated as a neurodegenerative receptor.65 Consequently, adenosine mainly effects brain functions through interaction with these 2 receptors, A1 and A2A,64 and a fine balance between inhibitory action of A1 and excitatory function of A2A receptors influences the neuromodulatory effect of adenosine.
