Adenosine A 2A receptor and ERK-driven impulsivity potentiates hippocampal neuroblast proliferation.

Dampened adenosine A2A receptor (A2A R) function has been implicated in addiction through enhancement of goal-directed behaviors. However, the contribution of the A2A R to the control of impulsive reward seeking remains unknown. Using mice that were exposed to differential reward of low rate (DRL) schedules during Pavlovian-conditioning, second-order schedule discrimination, and the 5-choice serial reaction time task (5-CSRTT), we demonstrate that deficits of A2A R function promote impulsive responses. Antagonism of the A2A R lowered ERK1 and ERK2 phosphorylation in the dorsal hippocampus (dHip) and potentiated impulsivity during Pavlovian-conditioning and the 5-CSRTT. Remarkably, inhibition of ERK1 and ERK2 phosphorylation by U0126 in the dHip prior to Pavlovian-conditioning exacerbated impulsive reward seeking. Moreover, we found decreased A2A R expression, and reduced ERK1 and ERK2 phosphorylation in the dHip of equilibrative nucleoside transporter type 1 (ENT1-/- ) null mice, which displayed exacerbated impulsivity. To determine whether impulsive response behavior is associated with hippocampal neuroblast development, we investigated expression of BrdU+ and doublecortin (DCX+ ) following 5-CSRTT testing. These studies revealed that impulsive behavior driven by inhibition of the A2A R is accompanied by increased neuroblast proliferation in the hippocampus.