Adenosine in the Central Nervous System: Effects on Neurotransmission and Neuroprotection

Adenosine is one of the principal neuromodulators in the brain and acts on four specific receptor subtypes: the A1, A2A, A2B and A3 receptors. Adenosine concentrations normally reached in the extracellular space are in the nanomolar range and may stimulate the high affinity A1 and A2A receptors. Inhibitory effects on neurotransmission are mediated mainly by A1 receptors while excitatory effects are mediated by A2A receptors. Adenosine has an overall net inhibitory effect on neurotransmission. Under normoxic conditions, A3 receptors do not exert a significant effect on neurotransmission and no data are available concerning the effect of A2B receptors. Given its ability to modulate neurotransmission, adenosine plays several physiological roles in the brain. It controls motility, acts as an endogenous anticonvulsant, and affects pain control, sleep, cognition and memory. It is also likely to be involved in the tonic modulation of affective states and consequently in social interaction and aggressive behaviour. Under pathological conditions, adenosine plays an important role in neuroprotective mechanisms interacting with A1 and A2A receptors and more recently there is evidence that A3 receptors are also involved. It has been demonstrated that A2A antagonists may be useful for control of symptoms and potentially for neuroprotection in Parkinson's disease. One possible approach in cerebral ischaemia is that of agents increasing locally the extracellular concentration of adenosine and of using A2A antagonists. Recent data support the putative utility of A2A receptor ligands in Huntington's disease.