Adenosine A3 receptor signaling in the central nervous system.

Adenosine A3 receptors are widely distributed in the central nervous system but are expressed at a low level and have lower affinity for adenosine in comparison to the A1 and A2A receptors. Nevertheless, they appear to tonically modulate motor activity as pointed out in A3 receptor-deleted mice. The role of A3 receptor in several pathophysiological conditions is often controversial. In conditions such as seizures or ischemia, when extracellular concentrations of adenosine increase, A3 receptors may contribute to neurotransmission and cell damage. A pro-convulsant effect of A3 receptor is feasible, especially in the immature brain, thus raising the possibility that A 3 receptor might facilitate seizure-induced neuronal damage and activity-dependent plastic changes. Most data support a pro-nociceptive role of A3 receptor involving both central nervous system and pro-inflammatory effects at peripheral tissues. The outcome of A3 receptor stimulation on synaptic transmission during hypoxic/ischemic phenomena appears to depend on the duration and intensity of the ischemic episode. While A3 receptor may play a protective role in the first phase of ischemia by decreasing synaptic transmission, prolonged A3AR stimulation by high adenosine concentrations could be pivotal in transforming the A 3AR-mediated effects from protective to injurious. Detrimental effects of A3AR activation may be due, at least in part, to increased excitoxicity. Glial A3AR stimulated by high adenosine levels caused by a prolonged central trauma may well be implicated in neuroinflammatory tissue responses.