Adenosine agonists favoured an intracellular Ca2+ rise in cultured type 1 astrocytes if the metabotropic glutamate receptors were concomitantly stimulated by (2S,1′s, 2′s)-2-(carboxycyclopropyl) glycine (l-CCG-I; group II agonist), quisqualate (group I agonist) or 1 -aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD; group VII agonist). Since the generation of a Ca2+ signal reflected a newly adopted adenosine A1 receptor action, we tested the possible consequence that the established opposing control of the cellular cAMP content by inhibitory A1 and stimulatory A2 receptor activation was also altered. During metabotropic receptor stimulation by L-CCG-I, quisqualate or t-ACPD, the non-selective adenosine agonist 2-chloroadenosine (CI-adenosine) caused a potentiated cAMP increase which markedly exceeded that produced by CI-adenosine alone. This cAMP potentiation resulted from altered and Ca2+-dependent A1/A2 receptor cooperation. It was abolished by A1 receptor blockade and could not be achieved in the presence of t-ACPD by the A1 agonist R(-)N6-(2-phenylisopropyl)-adenosine or by the A2 agonist 5′-N-ethyl carboxyamidoadenosine alone, but was obtained using their combination. The cAMP potentiation was blocked by intracellular Ca2+ chelation and the required A1 receptor action could be mimicked by a Ca2+ signal generated by the P2y receptor agonist adenosine 5β-(β-thio) diphosphate. The results support the conclusion that nanomolar concentrations of adenosine may influence astrocyte reactions by stimulating the Ca2+ and cAMP-dependent signalling cascade.