Adenosine Transporter ENT1 Regulates the Acquisition of Goal-Directed Behavior and Ethanol Drinking through A2A Receptor in the Dorsomedial Striatum

Adenosine signaling has been implicated in the pathophysiology of many psychiatric disorders including alcoholism. Striatal adenosine A 2A receptors (A 2A R) play an essential role in both ethanol drinking and the shift from goal-directed action to habitual behavior. However, direct evidence for a role of striatal A 2A R signaling in ethanol drinking and habit development has not been established. In the present study, we found that decreased A 2A R-mediated CREB activity in the dorsomedial striatum (DMS) enhanced initial behavioral acquisition of goal-directed behaviors and the vulnerability to progress to excessive ethanol drinking during operant conditioning in mice lacking ethanol-sensitive adenosine transporter ENT1 (ENT1 −/− ). Using mice expressing β-galactosidase (lacZ) under the control of seven repeated CRE sites in both genotypes (CRE-lacZ/ENT1 +/+ mice and CRE-lacZ/ENT1 −/− mice) and the dominant-negative form of CREB, we found that reduced CREB activity in the DMS was causally associated with decreased A 2A R signaling and increased goal-directed ethanol drinking. Finally, we have demonstrated that the A 2A R antagonist ZM241385 dampened protein kinase A activity–mediated signaling in the DMS and promoted excessive ethanol drinking in ENT1 +/+ mice, but not in ENT1 −/− mice. Our results indicate that A 2A R-mediated CREB signaling in the DMS is a key determinant in enhancing the development of goal-directed ethanol drinking in mice.