Use of knockout mice to explore CNS effects of adenosine.

The initial exploration using pharmacological tools of the role of adenosine receptors in the brain, concluded that adenosine released as such acted on AR to inhibit excitability and glutamate release from principal neurons throughout the brain and that adenosine A receptors (AR) were striatal-'specific' receptors controlling dopamine DR. This indicted AR as potential controllers of neurodegeneration and AR of psychiatric conditions. Global knockout of these two receptors questioned the key role of AR and instead identified extra-striatal AR as robust controllers of neurodegeneration. Furthermore, transgenic lines with altered metabolic sources of adenosine revealed a coupling of ATP-derived adenosine to activate AR and a role of AR as a hurdle to initiate neurodegeneration. Additionally, cell-selective knockout of AR unveiled the different roles of AR in different cell types (neurons/astrocytes) in different portions of the striatal circuits (dorsal versus lateral) and in different brain areas (hippocampus/striatum). Finally, a new transgenic mouse line with deletion of all adenosine receptors seems to indicate a major allostatic rather than homeostatic role of adenosine and may allow isolating P2R-mediated responses to unravel their role in the brain, a goal close to heart of Geoffrey Burnstock, to whom we affectionately dedicate this review.