Adenosine A(2A) receptor ligands: Effects on neuronal excitability

Our evolving understanding of the mechanisms involved in the actions of ade nosine on central neurons during the course of the past three decades has l argely been a consequence of certain specific advances. Early recognition t hat adenosine could either inhibit or stimulate cyclic AMP formation led to the concept of A(1) (inhibitory) or A(2) (stimulatory) receptors coupled v ia G proteins to adenylate cyclase. The early development of selective agon ists and antagonists for the A(1) binding site then stimulated a considerab le volume of pharmacological research on the actions of this receptor. Evid ence for the existence of more than one type of A(2) receptor also accumula ted, culminating in the cloning of two receptors, the high-affinity A(2A) a nd lower-affinity A(2B) receptors. The synthesis and availability of CGS 21 680, a selective agonist for the A(2A) receptor, made possible studies on t he pharmacological effects of its activation and the subsequent development of a series of A(2A) receptor antagonists has further clarified the roles that this receptor plays in the central nervous system. Whereas A(1) recept or activation inhibits synaptic transmission, primarily by decreasing excit atory neurotransmitter release from presynaptic nerve terminals, A(2A) rece ptor stimulation appears to enhance neurotransmitter release as a result of increased Ca2+ uptake. In brain slices, CGS 21680 facilitates excitatory t ransmission by increasing glutamate and acetylcholine release. However, whe n tested in vivo on central neurons by iontophoretic application, CGS 21680 has had a powerful depressant effect on neuronal activity which was blocke d by coapplication of an A(2A) receptor antagonist but not by a selective A (1) receptor antagonist. Further studies with the GABA(A) antagonists bicuc ulline and picrotoxin, which also block the inhibitory actions of CGS 21680 , revealed that in this instance A(2A) receptor activation facilitates GABA release, causing inhibition of neuronal firing. Whether the GABA release i s a consequence of enhanced excitatory drive to GABAergic neurons or is a d irect effect of an action at A(2A) receptors on GABAergic nerve terminals r emains uncertain. Drug Dev. Res. 52:331-336, 2001. (C) 2001 Wiley-Liss, Inc .