There is excellent evidence that adenosine plays a role in physiology and pathophysiology to modulate neural activity in the brain. For example, adenosine is known to act on adenosine A1 receptors to decrease neuronal firing and neurotransmitter release (1). This mechanism is of importance in limiting excessive neuronal activity and thereby, epileptic seizures (2, 3). Although the role of adenosine is rather uncontroversial, the origin of the adenosine mediating this anticonvulsant effect has been somewhat contentious. The work by Lovatt et al.(4) in PNAS not only clarifies that adenosine released from neurons is the important source, but it also raises more fundamental issues regarding the interactions between signaling through adenine nucleotides and adenosine and the role of astrocytes. The ability of adenosine to limit neurotransmission was first shown in the peripheral nervous system (motor neurons and sympathetic and parasympathetic nerves), and here, it was possible to provide good evidence that the source of adenosine was the effector tissue (5). Thus, the release of adenosine and the inhibition of neurotransmitter release after activation of the nerves could be mimicked by receptor agonists and reduced by receptor antagonists. To pinpoint the source of adenosine in the CNS was obviously more difficult, and it was not possible to determine conclusively if adenosine or adenine nucleotides were originally released. Based on a review of the literature in 1980 (5), it was concluded that nerve activity practically always releases adenine compounds and their metabolites. The release occurs both from nerve endings and from postsynaptic structures, but the latter source seems to be the more important. Both adenosine and adenine nucleotides seem to be released—their relative proportions varying with the tissue and the type of stimulus. This raises the possibility that adenosine and/or adenine nucleotides may act as local regulators of transmitter release. Since they are predominantly formed by the postsynaptic structures, the terms ‘transsynaptic modulation’and ‘retrograde transmission’have been coined to describe the phenomenon. The adenine derivatives are sufficiently potent as presynaptic inhibitors, at least in some tissues, to be active already under basal physiological conditions. In other instances adenine-derivatives may be important only when the local concentrations of adenosine are raised above the normal physiological range, for example by ischemia, or by extensive depolarization or by drugs.

There is good evidence that adenosine can be released from neurons after its concentration is raised intracellularly by an increase in activity or a reduction in energy supply. A general concept is that adenosine is released under conditions of distress and acts to limit the causes of its own release and/or the negative consequences thereof (6). To take but one