Dopamine D2 and Adenosine A2A Receptors Interaction on Ca2+ Current Modulation in a Rodent Model of Parkinsonism

Adenosine A(1) and A(2A) receptors are expressed in striatal projection neurons (SPNs). A(1) receptors are located in direct (dSPN) and indirect SPNs (iSNP). A(2A) receptors are only present in iSPNs. Dopamine D-2 receptors are also expressed in iSPNs and interactions between D-2 and A(2A) receptors have received attention. iSPNs activity increases during parkinsonism (PD) and A(2A) receptors may be responsible by enhancing Ca2+ currents (iCa(2+)). Therefore, A(2A) receptors blockade is a therapeutic approach. We asked whether A(2A) receptors need the interaction with D-2 receptors (D2R) to exert their actions. By using isolated and identified iSPNs to avoid indirect influences, we show that D2R action habilitates A(2A) receptors (A(2A)R) modulation. iCa(2+) through voltage gated Ca2+ channels (Ca-V) was used as a signal to observe this interaction. Voltage-clamp recordings in acutely dissociated iSPNs, current-clamp recordings in slices and calcium imaging in transgenic A(2A)-Cre mice, showed that D2R reduction in iCa(2+) endows A(2A)R to restore iCa(2+) on iSPNs showing an antagonistic interaction between D-2 and A(2A) receptors. A(2A) receptors were blocked by the antagonist istradefylline, however, this blockade differed in control and dopamine-depleted iSPNs: istradefylline reduced D2R modulation in parkinsonian animals as compared to controls. Calcium imaging recordings show that istradefylline occludes D2R actions in the parkinsonian circuitry and this effect depends on the order of drugs application. Thus, while D-2 activation enables A(2A) receptors action, blockade of A(2A)R induces a reduction in the action of D-2 agonists, confirming a complex interaction. Summary Statement A(2A) receptor required previous D-2 receptor activation to modulate Ca2+ currents. Istradefylline decreases pramipexole modulation on Ca2+ currents. Istradefylline reduces A(2A) + neurons activity in striatial microcircuit, but pramipexole failed to further reduce neuronal activity.