Role of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2a receptor signaling in the neostriatum

Adenosine is known to modulate the function of neostriatal neurons. Adenosine acting on A2A receptors increases the phosphorylation of dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32) at Thr34 (the cAMP-dependent protein kinase [PKA] site) in striatopallidal neurons, and opposes dopamine D2 receptor signaling. In contrast, the role of adenosine A1 receptors in the regulation of dopamine/DARPP-32 signaling is not clearly understood. Here, we investigated the effect of adenosine A1 receptors on D1, D2 and A2A receptor signaling using mouse neostriatal slices. An A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine (100 nM), caused a transient increase, followed by a transient decrease, in DARPP-32 Thr34 phosphorylation. Our data support the following model for the actions of the A1 receptor agonist. The A1 receptor-induced early increase in Thr34 phosphorylation was mediated by presynaptic inhibition of dopamine release, and the subsequent removal of tonic inhibition by D2 receptors of A2A receptor/Golf/cAMP/PKA signaling. The A1 receptor-induced late decrease in Thr34 phosphorylation was mediated by a postsynaptic Gi mechanism, resulting in inhibition of D1 and A2A receptor-coupled Golf/cAMP/PKA signaling in direct and indirect pathway neurons, respectively. In conclusion, A1 receptors play a major modulatory role in dopamine and adenosine receptor signaling.