Abstract The brain abundantly expresses adenosine receptors, which are involved in the regulation of neural activity, blood flow, and inflammation. In a previous study using our originally developed adenosine biosensor, we reported that hippocampal astrocytes release ATP upon water influx from the water channel AQP4, which is degraded extracellularly to increase adenosine (Yamashiro et al., 2017). On the other hand, the interaction between adenosine and dopamine is widely known, and when adenosine release from astrocytes is altered by inflammation or other factors, abnormal dopamine neurotransmission and related ataxia and psychiatric disorders may develop. In the present study, we examined pathological changes in adenosine or dopamine release in depressive-like behavior that develops as a symptom of cocaine withdrawal. The results showed that A 1 receptor inhibitors and AQP4 gene disruption suppressed depressive-like behavior. In the striatum, AQP4-dependent adenosine release inhibited dopamine release via A 1 receptors, and cocaine inhibited dopamine release by increasing this adenosine release. In contrast, in the medial frontal cortex, AQP4-dependently released adenosine enhanced dopamine release via A 1 receptors, and cocaine abolished this adenosine effect. Furthermore, adenosine action was restored in AQP4 knockout mice, suggesting that cocaine reduced A 1 receptor function via AQP4-dependent adenosine. In conclusion, astrocytes modulate dopaminergic neurotransmission through AQP4-mediated adenosine release, and this disruption leads to depression-like behavior.

Crosstalk between AQP4-dependent ATP/Adenosine release and dopamine neurotransmission in depressive behavior during cocaine withdrawal