Our previous studies have shown that the water influx via astrocytic AQP4 induces the release of ATP and subsequent increase of extracellular adenosine. Since antagonistic interactions between adenosine and dopamine have been shown by biochemical and pharmacological studies, the present study investigated the possibility that the AQP4-dependent adenosine increase interacts with dopamine neurotransmission, focusing on the effects of cocaine. The stimulus effect of acute cocaine treatment was abolished in AQP4 ko mice, while mice treated with caffeine for one week showed the increase of the stimulus effect. In addition, it was found that the evoked-dopamine release in the striatum was inhibited by adenosine, while enhanced by adenosine receptor antagonists. In addition, AQP4 ko mice showed the similar increase of dopamine. Thus, it was suggested that a single dose of cocaine lacks stimulus effect because AQP4-dependent adenosine increase, which is downregulated by continuous cocaine treatment, inhibits dopamine release. AQP4 ko mice were also lacked depressive behavior during cocaine withdrawal, which is sensitive to adenosine receptor antagonists. Furthermore, cocaine withdrawal reduced the evoked-dopamine release in the striatum, but it was not the case in AQP4 ko mice. Thus, it was suggested that AQP4-dependent adenosine increase is upregulated by cocaine withdrawal, resulting in excessive suppression of dopamine neurotransmission and depressive behavior. Overall, the present results suggest that striatal dopamine release is suppressed by AQP4-dependent adenosine increase, which is down-regulated by continuous cocaine treatment, while up-regulated by cocaine withdrawal.