Different modulation of inhibitory and stimulatory pathways mediated by adenosine after chronic in vivo agonist exposure

After 6 days of in vivo treatment with two selective adenosine receptor agonists, 5′-N-ethylcarboxamido adenosine (NECA) and R-N6-phenylisopropiladenosine (R-PIA), we investigated their effects on adenosine receptors/adenylyl cyclase system in synaptic plasma membranes isolated from rat brain. NECA treatment caused a significant loss of NECA-stimulated adenylyl cyclase activity, suggesting a desensitization of the adenosine A2 receptors-mediated pathway. No significant differences in total adenosine A2 receptors were observed, but Gs protein levels were decreased, suggesting Gs down-regulation as a mechanism for desensitization. On the other hand, NECA treatment caused a significant decrease in high-affinity adenosine A1 receptors population; however, no changes in CHA-inhibited adenylyl cyclase activity or Gi protein level were observed. Finally, when we studied the effects of R-PIA, a selective adenosine A1 receptor agonist, on stimulatory pathway of adenosine, low-affinity adenosine A2 binding sites were decreased without affecting the functionality of the pathway. These results show that adenosine A1 and A2 receptors are modulated in a different way after chronic agonist exposure and suggest the existence of cross-talk mechanisms between both stimulatory an inhibitory pathways mediated by adenosine.