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-N-6-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 A(2) receptors-mediated pathway. No significant differences in total adenosine A(2) receptors were observed, but G(s) protein levels were decreased, suggesting G(s) down-regulation as a mechanism for desensitization. On the other hand, NECA treatment caused a significant decrease in high-affinity adenosine A(1) 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 A(1) receptor agonist, on stimulatory pathway of adenosine, low-affinity adenosine A(2) binding sites were decreased without affecting the functionality of the pathway. These results show that adenosine A(1) and A(2) 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. (C) 2004 Elsevier B.V. All rights reserved.