A1 and A2A Receptors Modulate Spontaneous Adenosine but Not Mechanically Stimulated Adenosine in the Caudate

Adenosine is a neuromodulator, and rapid increases in adenosine in the brain occur spontaneously or after mechanical stimulation. However, the regulation of rapid adenosine by adenosine receptors is unclear, and understanding it would allow better manipulation of neuromodulation. The two main adenosine receptors in the brain are A 1 receptors, which are inhibitory, and A 2A receptors, which are excitatory. Here, we investigated the regulation of spontaneous adenosine and mechanically stimulated adenosine by adenosine receptors, using global A 1 or A 2A knockout mice. Results were compared in vivo and in brain slices' models. A 1 KO mice have increased frequency of spontaneous adenosine events, but no change in the average concentration of an event, while A 2A KO mice had no change in frequency but increased average event concentration. Thus, both A 1 and A 2A self-regulate spontaneous adenosine release; however, A 1 acts on the frequency of events, while A 2A receptors regulate concentration. The trends are similar both in vivo and slices, so brain slices are a good model system to study spontaneous adenosine release. For mechanically stimulated adenosine, there was no effect of A 1 or A 2A KO in vivo , but in brain slices, there was a significant increase in concentration evoked in A 1 KO mice. Mechanically stimulated release was largely unregulated by A 1 and A 2A receptors, likely because of a different release mechanism than spontaneous adenosine. Thus, A 1 receptors affect the frequency of spontaneous adenosine transients, and A 2A receptors affect the concentration. Therefore, future studies could probe drug treatments targeting A 1 and A 2A receptors to increase rapid adenosine neuromodulation.