Adenosine A_2A receptor and ERK-driven impulsivity potentiates hippocampal neuroblast proliferation

Dampened adenosine A_2A receptor (A_2AR) function has been implicated in addiction through enhancement of goal-directed behaviors. However, the contribution of the A_2AR 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 A_2AR function promote impulsive responses. Antagonism of the A_2AR 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 A_2AR 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 A_2AR is accompanied by increased neuroblast proliferation in the hippocampus.