Adenosine A2A receptor and ERK-driven impulsivity potentiates hippocampal neuroblast proliferation

A Oliveros,S Choi,M-H Jang,A Cui,D Lindberg,D Hinton,C H Cho,D-S Choi

doi:10.1038/tp.2017.64

Abstract

Dampened adenosine A2A receptor (A2AR) function has been implicated in addiction through enhancement of goal-directed behaviors. However, the contribution of the A2AR 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 A2AR function promote impulsive responses. Antagonism of the A2AR 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 A2AR 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 A2AR is accompanied by increased neuroblast proliferation in the hippocampus.

Highlights

The dorsal hippocampus and nucleus accumbens (NAc) are constituents of a neural circuit that regulates adaptability and survival.[1]
We investigated a possible link between dysregulation of the A2A receptor (A2AR) in relation to neuroblast development within the hippocampal dentate gyrus (DG)
To our knowledge, our findings are the first to demonstrate a novel role for the A2AR in impulsivity and immature neuroblast proliferation, both of which may be factors underlying the process of neurogenesis in reward seeking behaviors

Summary

INTRODUCTION

The dorsal hippocampus (dHip) and nucleus accumbens (NAc) are constituents of a neural circuit that regulates adaptability and survival.[1] maladaptation of hippocampal-striatal circuits contribute to the development of impulsivity, compulsivity and addiction.[2] Differential reinforcement of low rates of behavior (DRL) schedules have revealed the hippocampus to be a regulatory neural substrate in impulsivity and reward acquisition[3,4] in both human and animal models.[5,6] Alcoholinduced impulsivity in humans[7] and rodents[8] are partially driven by contextual evocation of drug-induced euphoria to cues These contextual associations are largely regulated by the dHip, which has an instrumental role in controlling cue-induced drug seeking and relapse in substance use disorders.[9,10]. To our knowledge, our findings are the first to demonstrate a novel role for the A2AR in impulsivity and immature neuroblast proliferation, both of which may be factors underlying the process of neurogenesis in reward seeking behaviors

MATERIALS AND METHODS

RESULTS

CONFLICT OF INTEREST