Dopamine D and Adenosine A Receptors Interaction on Ca Current Modulation in a Rodent Model of Parkinsonism

Abstract

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 Ca 2+ 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 (D 2 R) to exert their actions. By using isolated and identified iSPNs to avoid indirect influences, we show that D 2 R action habilitates A 2A receptors (A 2A R) modulation. iCa 2+ through voltage gated Ca 2+ 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 D 2 R 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 D 2 R modulation in parkinsonian animals as compared to controls. Calcium imaging recordings show that istradefylline occludes D 2 R 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 Ca 2+ currents. Istradefylline decreases pramipexole modulation on Ca 2+ currents. Istradefylline reduces A 2A + neurons activity in striatial microcircuit, but pramipexole failed to further reduce neuronal activity.