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Adenosine A2A receptor ligands: Effects on neuronal excitability

Our evolving understanding of the mechanisms involved in the actions of adenosine on central neurons during the course of the past three decades has largely been a consequence of certain specific advances. Early recognition that adenosine could either inhibit or stimulate cyclic AMP formation led to the concept of A1 (inhibitory) or A2 (stimulatory) receptors coupled via G proteins to adenylate cyclase. The early development of selective agonists and antagonists for the A1 binding site then stimulated a considerable volume of pharmacological research on the actions of this receptor. Evidence for the existence of more than one type of A2 receptor also accumulated, culminating in the cloning of two receptors, the high‐affinity A2A and lower‐affinity A2B receptors. The synthesis and availability of CGS 21680, a selective agonist for the A2A receptor, made possible studies on the pharmacological effects of its activation and the subsequent development of a series of A2A receptor antagonists has further clarified the roles that this receptor plays in the central nervous system. Whereas A1 receptor activation inhibits synaptic transmission, primarily by decreasing excitatory neurotransmitter release from presynaptic nerve terminals, A2A receptor stimulation appears to enhance neurotransmitter release as a result of increased Ca2+ uptake. In brain slices, CGS 21680 facilitates excitatory transmission by increasing glutamate and acetylcholine release. However, when tested in vivo on central neurons by iontophoretic application, CGS 21680 has had a powerful depressant effect on neuronal activity which was blocked by coapplication of an A2A receptor antagonist but not by a selective A1 receptor antagonist. Further studies with the GABAA antagonists bicuculline and picrotoxin, which also block the inhibitory actions of CGS 21680, revealed that in this instance A2A receptor activation facilitates GABA release, causing inhibition of neuronal firing. Whether the GABA release is a consequence of enhanced excitatory drive to GABAergic neurons or is a direct effect of an action at A2A receptors on GABAergic nerve terminals remains uncertain. Drug Dev. Res. 52:331–336, 2001. © 2001 Wiley‐Liss, Inc.