ENT1‐Mediated Adenosine A 2A R Signaling Promotes Impulsive Responses During Acquisition of Conditioned Reward Seeking

Abstract

Although adenosine plays an essential role in hippocampal neuronal activity, it was unclear whether an ethanol-sensitive adenosine transporter ENT1 (equilibrative nucleoside transporter) regulates cue-induced learning of addictive behaviors. Adenosine signaling has been implicated in ethanol-seeking behaviors in mice lacking ENT1, through decreased A2A adenosine receptor (A2AR) function. To test if adenosine signaling regulates impulsive behaviors, which may lead to aberrant alcohol use, we performed a random interval differential reward of low rate (DRL) Pavlovian conditioning task. Our results indicate that ENT1 nullmice displayed increased impulsive responses and shorter reaction times during reward retrieval. Interestingly, following Pavlovian conditioning, we observed increased ERK signaling and reduced A2AR expression in the hippocampus of ENT1 null mice compared to wild-type littermates. Consistently, an A2AR-specific antagonist (ZM-241385) increased ERK activity in the hippocampus and increased impulsive behaviors similar to ENT1 null mice, suggesting a possible causal relationship between dampened A2AR signaling and increased impulsive responding to reward.