Astrocytic equilibrative nucleoside transporter type 1 upregulations in the dorsomedial and dorsolateral striatum distinctly coordinate goal-directed and habitual ethanol-seeking behaviours in mice

Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal-directed and habitual reward-seeking behaviours, respectively. Previously, our study shows that the ethanol-sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol-drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal-directed and habitual ethanol-seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4 days of random interval (RI), mice exhibited habitual seeking for 10S, but goal-directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E-seeking behaviour on a fixed ratio (FR) for 6 days and RI for 8 days. On the other hand, during FR and the first 4 days of RI schedules, mice showed goal-directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4 days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal-directed reward-seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward-seeking behaviours.