In the hippocampus, the neuromodulatory role of adenosine depends on a balance between inhibitory A 1 responses and facilitatory A 2 A responses. Since the presynaptic effects of hippocampal inhibitory A 1 adenosine receptors are mostly mediated by inhibition of Ca 2 + channels, we now investigated whether presynaptic facilitatory A 2 A adenosine receptors would modulate calcium influx in the hippocampus. The mixed A 1 /A 2 agonist, 2-chloroadenosine (CADO; 1 μM) inhibited veratridine (20 μM)-evoked 4 5 Ca 2 + influx into hippocampal synaptosomes of the CA1 or CA3 areas by 24.2±4.5% and 17.2±5.8%, respectively. In the presence of the A, antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), the inhibitory effect of CADO (1 μM) on 4 5 Ca 2 + influx was prevented in CA1 synaptosomes, but was converted into a facilitatory effect (14.2±6.7%) in CA3 synaptosomes. The A 2 A agonist, CGS 21680 (3-30 nM) facilitated 4 5 Ca 2 + influx in CA3 synaptosomes, with a maximum increase of 22.9±3.9% at 10 nM, and was virtually devoid of effect in CA1 synaptosomes. This facilitatory effect of CGS 21680 (10 nM) in CA3 synaptosomes was prevented by the A 2 A antagonist 8-(3-chlorostyryl)caffeine (CSC; 200 nM), but not by the A 1 antagonist, DPCPX (20 or 100 nM). The facilitatory effect of CGS 21680 on 4 5 Ca 2 + uptake by CA3 synaptosomes was prevented by the class A calcium channel blocker, ω-agatoxin-IVA (200 nM). These results indicate that presynaptic adenosine A 2 A receptors facilitate calcium influx in the CA3 but not the CA1 area of the rat hippocampus through activation of class A calcium channels.