Summary In the vertebrate central nervous system (CNS) the modulation of synaptic transmission by metabotropic or ionotropic receptors is an important source of control and dynamical adjustment in synaptic activity and can contribute to synergistic or antagonistic effects. Adenosine is released from most cells, including Sneurons and glial cells. Once in the extracellular space, adenosine modifies cell functioning by operating G-protein-coupled receptors. In general, adenosine has been found to act in concert with other hormones or neurotransmitters in either an inhibitory or a stimulatory way. From the four cloned adenosine receptors (A 1 Rs, A 2A Rs, A 2B Rs and A 3 R), A 1 Rs and A 2A Rs are the main targets for the physiological effects of adenosine in the brain. A 1 R is a prototype of G-protein-coupled receptor able to form heterotypic interactions with other members of metabotropic and ionic receptors. The development of effective agonists, antagonists and in addition, gene-targeted mice deficient in the expression of each receptor subtype has made it possible to clarify the functional role with respect to synergistic effects with other receptors in both physiological and pathophysiological conditions. It is becoming increasingly obvious that the modulatory role of adenosine is related to the ability of A 1 Rs and A 2A Rs heteromerize with themselves and with other receptors, such as dopamine, glutamate or GABA. These interactions between adenosine receptors and other receptors for neurotransmitters might contribute to a fine-tuning of neuronal function, and therefore, to neuroprotection.